Total synthesis and biological evaluation of the tetramic acid based natural product harzianic acid and its stereoisomers

Financial support for this project was provided by Cancer Research UK (Grant No. C21383/A6950)The bioactive natural product harzianic acid was prepared for the first time in just six steps (longest linear sequence) with an overall yield of 22%. The identification of conditions to telescope amide bond formation and a Lacey-Dieckmann reaction into one pot proved important. The three stereoisomers of harzianic acid were also prepared, providing material for comparison of their biological activity. While all of the isomers promoted root growth, improved antifungal activity was unexpectedly associated with isomers in the enantiomeric series opposite that of harzianic acid.Publisher PDFPeer reviewe

Accumulation of driver and passenger mutations during tumor progression

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a novel mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development - providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research

Generation of entangled states of two atoms inside a leaky cavity

An in-depth theoretical study is carried out to examine the quasi-deterministic entanglement of two atoms inside a leaky cavity. Two $\Lambda$-type three-level atoms, initially in their ground states, may become maximally entangled through the interaction with a single photon. By working out an exact analytic solution, we show that the probability of success depends crucially on the spectral function of the injected photon. With a cavity photon, one can generate a maximally entangled state with a certain probability that is always less than 50%. However, for an injected photon with a narrower spectral width, this probability can be significantly increased. In particular, we discover situations in which entanglement can be achieved in a single trial with an almost unit probability

Full capacitance-matrix effects in driven Josephson-junction arrays

We study the dynamic response to external currents of periodic arrays of Josephson junctions, in a resistively capacitively shunted junction (RCSJ) model, including full capacitance-matrix effects}. We define and study three different models of the capacitance matrix $C_{\vec{r},\vec{r}'}$: Model A includes only mutual capacitances; Model B includes mutual and self capacitances, leading to exponential screening of the electrostatic fields; Model C includes a dense matrix $C_{\vec{r},\vec{r}'}$ that is constructed approximately from superposition of an exact analytic solution for the capacitance between two disks of finite radius and thickness. In the latter case the electrostatic fields decay algebraically. For comparison, we have also evaluated the full capacitance matrix using the MIT fastcap algorithm, good for small lattices, as well as a corresponding continuum effective-medium analytic evaluation of a finite voltage disk inside a zero-potential plane. In all cases the effective $C_{\vec{r},\vec{r}'}$ decays algebraically with distance, with different powers. We have then calculated current voltage characteristics for DC+AC currents for all models. We find that there are novel giant capacitive fractional steps in the I-V's for Models B and C, strongly dependent on the amount of screening involved. We find that these fractional steps are quantized in units inversely proportional to the lattice sizes and depend on the properties of $C_{\vec{r},\vec{r}'}$. We also show that the capacitive steps are not related to vortex oscillations but to localized screened phase-locking of a few rows in the lattice. The possible experimental relevance of these results is also discussed.Comment: 12 pages 18 Postscript figures, REVTEX style. Paper to appear in July 1, Vol. 58, Phys. Rev. B 1998 All PS figures include

Signatures of early frailty in the gut microbiota

Background: Frailty is arguably the biggest problem associated with population ageing, and associates with gut microbiome composition in elderly and care-dependent individuals. Here we characterize frailty associations with the gut microbiota in a younger community dwelling population, to identify targets for intervention to encourage healthy ageing. Method: We analysed 16S rRNA gene sequence data derived from faecal samples obtained from 728 female twins. Frailty was quantified using a frailty index (FI). Mixed effects models were used to identify associations with diversity, operational taxonomic units (OTUs) and taxa. OTU associations were replicated in the Eldermet cohort. Phenotypes were correlated with modules of OTUs collapsed by co-occurrence. Results: Frailty negatively associated with alpha diversity of the gut microbiota. Models considering a number of covariates identified 637 OTUs associated with FI. Twenty-two OTU associations were significant independent of alpha diversity. Species more abundant with frailty included Eubacterium dolichum and Eggerthella lenta. A Faecalibacterium prausnitzii OTU was less abundant in frailer individuals, and retained significance in discordant twin analysis. Sixty OTU associations were replicated in the Eldermet cohort. OTU co-occurrence modules had mutually exclusive associations between frailty and alpha diversity. Conclusions: There was a striking negative association between frailty and gut microbiota diversity, underpinned by specific taxonomic associations. Whether these relationships are causal or consequential is unknown. Nevertheless, they represent targets for diagnostic surveillance, or for intervention studies to improve vitality in ageing

X-ray absorption spectroscopy study of diluted magnetic semiconductors: Zn1-xMxSe (M = Mn, Fe, Co) and Zn1-xMnxY (Y = Se, Te)

We have investigated 3d electronic states of doped transition metals in II-VI diluted magnetic semiconductors, Zn1-xMxSe (M = Mn, Fe, Co) and Zn1-xMnxY (Y = Se, Te), using the transition-metal L2,3-edge X-ray absorption spectroscopy (XAS) measurements. In order to explain the XAS spectra, we employed a tetragonal cluster model calculation, which includes not only the full ionic multiplet structure but also configuration interaction (CI). The results show that CI is essential to describe the experimental spectra adequately, indicating the strong hybridization between the transition metal 3d and the ligand p orbitals. In the study of Zn1-xMnxY (Y = Se, Te), we also found considerable spectral change in the Mn L2,3-edge XAS spectra for different ligands, confirming the importance of the hybridization effects in these materials.Comment: This paper consists of 22 pages including 4 figures. This paper is submitted to Physical Review

Quantum noise in the position measurement of a cavity mirror undergoing Brownian motion

We perform a quantum theoretical calculation of the noise power spectrum for a phase measurement of the light output from a coherently driven optical cavity with a freely moving rear mirror. We examine how the noise resulting from the quantum back action appears among the various contributions from other noise sources. We do not assume an ideal (homodyne) phase measurement, but rather consider phase modulation detection, which we show has a different shot noise level. We also take into account the effects of thermal damping of the mirror, losses within the cavity, and classical laser noise. We relate our theoretical results to experimental parameters, so as to make direct comparisons with current experiments simple. We also show that in this situation, the standard Brownian motion master equation is inadequate for describing the thermal damping of the mirror, as it produces a spurious term in the steady-state phase fluctuation spectrum. The corrected Brownian motion master equation [L. Diosi, Europhys. Lett. {\bf 22}, 1 (1993)] rectifies this inadequacy.Comment: 12 pages revtex, 2 figure

Social-ecological, motivational and volitional factors for initiating and maintaining physical activity in the context of HIV

Sport and exercise can have several health benefits for people living with HIV. These benefits can be achieved through different types of physical activity, adapting to disease progression, motivation and social-ecological options. However, physical activity levels and adherence to exercise are generally low in people living with HIV. At the same time, high drop-out rates in intervention studies are prevalent; even though they often entail more favourable conditions than interventions in the natural settings. Thus, in the framework of an intervention study, the present study aims to explore social-ecological, motivational and volitional correlates of South African women living with HIV with regard to physical activity and participation in a sport and exercise health promotion programme. The qualitative data was produced in the framework of a non-randomised pre-post intervention study that evaluated structure, processes and outcomes of a 10-week sport and exercise programme. All 25 participants of the programme were included in this analysis, independent of compliance. Data was produced through questionnaires, participatory group discussions, body image pictures, research diaries and individual semi-structured interviews. All participants lived in a low socioeconomic, disadvantaged setting. Hence, the psychological correlates are contextualised and social-ecological influences on perception and behaviour are discussed. The results show the importance of considering social-cultural and environmental influences on individual motives, perceptions and expectancies, the fear of disclosure and stigmatisation, sport and exercise-specific group dynamics and self-supporting processes. Opportunities and strategies to augment physical activity and participation in sport and exercise programmes in the context of HIV are discussed.Scopu

MRI of the lung (3/3)-current applications and future perspectives

BACKGROUND: MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. METHODS: Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. RESULTS: In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. CONCLUSION: New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations

Coherent coupling of two quantum dots embedded in an Aharonov-Bohm ring

We define two laterally gated small quantum dots (~ 15 electrons) in an Aharonov-Bohm geometry in which the coupling between the two dots can be broadly changed. For weakly coupled quantum dots we find Aharonov-Bohm oscillations. In an intermediate coupling regime we concentrate on the molecular states of the double dot and extract the magnetic field dependence of the coherent coupling.Comment: 6 pages, 4 figure