Measuring multiple 17O–13C J-couplings in naphthalaldehydic acid: a combined solid state NMR and density functional theory approach

A combined multinuclear solid state NMR and gauge included projected augmented wave, density functional theory (GIPAW DFT) computational approach is evaluated to determine the four heteronuclear 1J(13C,17O) couplings in solid 17O enriched naphthalaldehydic acid. Direct multi-field 17O magic angle spinning (MAS), triple quantum MAS (3QMAS) and double rotation (DOR) experiments are initially utilised to evaluate the accuracy of the DFT approximations used in the calculation of the isotropic chemical shifts (diso), quadrupole coupling constants (CQ) and asymmetry (ZQ) parameters. These combined approaches give diso values of 313, 200 and 66 ppm for the carbonyl (CQO), ether (–O–) and hydroxyl (–OH) environments, respectively, with the corresponding measured quadrupole products (PQ) being 8.2, 9.0 and 10.6 MHz. The geometry optimised DFT structure derived using the CASTEP code gives firm agreement with the shifts observed for the ether (diso = 223, PQ = 9.4 MHz) and hydroxyl (diso = 62, PQ = 10.5 MHz) environments but the unoptimised experimental XRD structure has better agreement for the carbonyl group (diso = 320, PQ = 8.3 MHz). The determined diso and ZQ values are shown to be consistent with bond lengths closer to 1.222 Å (experimental length) rather than the geometry optimised length of 1.238 Å. The geometry optimised DFT 1J(13C,17O) coupling to the hydroxyl is calculated as 20 Hz and the couplings to the ether were calculated to be 37 (O–CQO) and 32 (O–C–OH) Hz. The scalar coupling parameters for the unoptimised experimental carbonyl group predict a 1J(13C,17O) value of 28 Hz, whilst optimisation gives a value of 27 Hz. These calculated 1J(13C,17O) couplings, together with estimations of the probability of each O environment being isotopically labelled (determined by electrospray ionisation mass spectrometry) and the measured refocussable transverse dephasing (T2 0) behaviour, are combined to simulate the experimental decay behaviour. Good agreement between the measured and calculated decay behaviour is observed

Structural characterization and physical properties of P2O5-CaO-Na2O-TiO2 glasses by Fourier transform infrared, Raman and solid-state magic angle spinning nuclear magnetic resonance spectroscopies.

Phosphate-based glasses have been investigated for tissue engineering applications. This study details the properties and structural characterization of titanium ultra-phosphate glasses in the 55(P(2)O(5))-30(CaO)-(25-x)(Na(2)O)-x(TiO(2)) (0≤x≤5) system, which have been prepared via melt-quenching techniques. Structural characterization was achieved by a combination of X-ray diffraction (XRD), and solid-state nuclear magnetic resonance, Raman and Fourier transform infrared spectroscopies. Physical properties were also investigated using density, degradation and ion release studies; additionally, differential thermal analysis was used for thermal analysis of these glasses. The results show that with the addition of TiO(2) the density and glass transition temperature increased whereas the degradation and ion release properties are decreased. From XRD data, TiP(2)O(7) and CaP(2)O(6) were detected in 3 and 5 mol.% TiO(2)-containing glasses. Magic angle spinning nuclear magnetic resonance results confirmed that as TiO(2) is incorporated into the glass; the amount of Q(3) increases as the amount of Q(2) consequently decreases, indicating increasing polymerization of the phosphate network. Spectroscopy results also showed that the local structure of glasses changes with increasing TiO(2) content. As TiO(2) is incorporated into the glass, the phosphate connectivity increases, indicating that the addition of TiO(2) content correlates unequivocally with an increase in glass stability

The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer

Background: Using data from a large phase III study of previously treated advanced non-small-cell lung cancer (NSCLC) that showed similar efficacy for pemetrexed and docetaxel, this retrospective analysis evaluates the impact of first-line chemotherapy on the outcome of second-line chemotherapy. Patients and methods: In all, 571 patients with advanced NSCLC were randomly assigned to receive pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 on day 1 of a 21-day cycle. Comparisons were made based on type of first-line therapy [gemcitabine + platinum (GP), taxane + platinum (TP), or other therapies (OT)], response to initial therapy, time since initial therapy, and clinical characteristics. The two second-line treatment groups were pooled for this analysis due to similar efficacy and were assumed to have no interaction with the first-line therapies. Results: Baseline characteristics were generally balanced. By multivariate analysis, gender, stage at diagnosis, performance status (PS), and best response to first-line therapy significantly influenced overall survival (OS). Additional factors by univariate analysis, histology, and time elapsed from first- to second-line therapy significantly influenced OS. Conclusions: Future trials in the second-line setting should stratify patients by gender, stage at diagnosis, PS, and best response to first-line therap

Moku virus; a new Iflavirus found in wasps, honey bees and Varroa

There is an increasing global trend of emerging infectious diseases (EIDs) affecting a wide range of species, including honey bees. The global epidemic of the single stranded RNA Deformed wing virus (DWV), driven by the spread of Varroa destructor has been well documented. However, DWV is just one of many insect RNA viruses which infect a wide range of hosts. Here we report the full genome sequence of a novel Iflavirus named Moku virus (MV), discovered in the social wasp Vespula pensylvanica collected in Hawaii. The novel genome is 10,056 nucleotides long and encodes a polyprotein of 3050 amino acids. Phylogenetic analysis showed that MV is most closely related to Slow bee paralysis virus (SBPV), which is highly virulent in honey bees but rarely detected. Worryingly, MV sequences were also detected in honey bees and Varroa from the same location, suggesting that MV can also infect other hymenopteran and Acari hosts

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Assessing Internet addiction using the parsimonious Internet addiction components model - a preliminary study [forthcoming]

Internet usage has grown exponentially over the last decade. Research indicates that excessive Internet use can lead to symptoms associated with addiction. To date, assessment of potential Internet addiction has varied regarding populations studied and instruments used, making reliable prevalence estimations difficult. To overcome the present problems a preliminary study was conducted testing a parsimonious Internet addiction components model based on Griffiths’ addiction components (2005), including salience, mood modification, tolerance, withdrawal, conflict, and relapse. Two validated measures of Internet addiction were used (Compulsive Internet Use Scale [CIUS], Meerkerk et al., 2009, and Assessment for Internet and Computer Game Addiction Scale [AICA-S], Beutel et al., 2010) in two independent samples (ns = 3,105 and 2,257). The fit of the model was analysed using Confirmatory Factor Analysis. Results indicate that the Internet addiction components model fits the data in both samples well. The two sample/two instrument approach provides converging evidence concerning the degree to which the components model can organize the self-reported behavioural components of Internet addiction. Recommendations for future research include a more detailed assessment of tolerance as addiction component

Comparative assessment of clinical rating scales in Wilson’s disease

Background: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess two clinical rating scales for WD, the Unified Wilson’s Disease Rating Scale (UWDRS) and the Global Assessment Scale for Wilson’s disease (GAS for WD), and to test the feasibility of the patient reported part of the UWDRS neurological subscale (termed the “minimal UWDRS”). Methods: In this prospective, monocentric, cross-sectional study, 65 patients (median age 35 [range: 15–62] years; 33 female, 32 male) with treated WD were scored according to the two rating scales. Results: The UWDRS neurological subscore correlated with the GAS for WD Tier 2 score (r = 0.80; p < 0.001). Correlations of the UWDRS hepatic subscore and the GAS for WD Tier 1 score with both the Model for End Stage Liver Disease (MELD) score (r = 0.44/r = 0.28; p < 0.001/p = 0.027) and the Child-Pugh score (r = 0.32/r = 0.12; p = 0.015/p = 0.376) were weak. The “minimal UWDRS” score significantly correlated with the UWDRS total score (r = 0.86), the UWDRS neurological subscore (r = 0.89), and the GAS for WD Tier 2 score (r = 0.86). Conclusions: The UWDRS neurological and psychiatric subscales and the GAS for WD Tier 2 score are valuable tools for the clinical assessment of WD patients. The “minimal UWDRS” is a practical prescreening tool outside scientific trials

Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Patients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI.</p> <p>Case presentation</p> <p>Two patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib.</p> <p>Conclusion</p> <p>NSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure.</p

Stakeholder engagement in the city branding process

This paper explores perceptions of stakeholder engagement in the city branding process from the perspective of two post-industrial cities: Sheffield, UK and Essen, Germany. This qualitative research utilises a multi case study approach, which allowed for semi-structure interviews and semiotics to be used. Preliminary findings highlight that there are four stakeholder ‘levels’. Each of these stakeholder groupings is involved in the city branding process to some extend. Findings suggest that the degree of involvement strongly depends on the primary stakeholders, who are seen as key decision-makers in the branding process. These primary stakeholders select other stakeholders that ‘can’ be involved in the branding process. Although this may be beneficial it is vital to provide more opportunities and incorporate stakeholders that are willing to participate in the branding process. Alienating stakeholders may also lead to losing parts of an identity that is based on heritage. The focus is on two cities with a highly industrialised background, thus findings may not be applicable to cities without this heritage. The paper looks at both stakeholder engagement and city branding, thereby proposing four layers of stakeholder involvement in the city branding process

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCβ inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription–PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3β and Akt phosphorylation, which was additionally reduced by drug combination (−58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (>50% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients