Mechanisms of dynamic nuclear polarization in insulating solids

Dynamic nuclear polarization (DNP) is a technique used to enhance signal intensities in NMR experiments by transferring the high polarization of electrons to their surrounding nuclei. The past decade has witnessed a renaissance in the development of DNP, especially at high magnetic fields, and its application in several areas including biophysics, chemistry, structural biology and materials science. Recent technical and theoretical advances have expanded our understanding of established experiments: for example, the cross effect DNP in samples spinning at the magic angle. Furthermore, new experiments suggest that our understanding of the Overhauser effect and its applicability to insulating solids needs to be re-examined. In this article, we summarize important results of the past few years and provide quantum mechanical explanations underlying these results. We also discuss future directions of DNP and current limitations, including the problem of resolution in protein spectra recorded at 80–100 K.National Institute for Biomedical Imaging and Bioengineering (U.S.) (EB-002804)National Institute for Biomedical Imaging and Bioengineering (U.S.) (EB-001960)National Institute for Biomedical Imaging and Bioengineering (U.S.) (EB-003151)National Institute for Biomedical Imaging and Bioengineering (U.S.) (EB-002026

Characterization of Zika virus endocytic pathways in human glioblastoma cells

Zika virus (ZIKV) infections can cause microcephaly and neurological disorders. However, the early infection events of ZIKV in neural cells remain to be characterized. Here, by using a combination of pharmacological and molecular approaches and the human glioblastoma cell T98G as a model, we first observed that ZIKV infection was inhibited by chloroquine and NH4Cl, indicating a requirement of low intracellular pH. We further showed that dynamin is required as the ZIKV entry was affected by the specific inhibitor dynasore, small interfering RNA (siRNA) knockdown of dynamin, or by expressing the dominant-negative K44A mutant. Moreover, the ZIKV entry was significantly inhibited by chlorpromazine, pitstop2, or siRNA knockdown of clathrin heavy chain, indicating an involvement of clathrin-mediated endocytosis. In addition, genistein treatment, siRNA knockdown of caveolin-1, or overexpression of a dominant-negative caveolin mutant impacted the ZIKV entry, with ZIKV particles being observed to colocalize with caveolin-1, implying that caveola endocytosis can also be involved. Furthermore, we found that the endocytosis of ZIKV is dependent on membrane cholesterol, microtubules, and actin cytoskeleton. Importantly, ZIKV infection was inhibited by silencing of Rab5 and Rab7, while confocal microscopy showed that ZIKV particles localized in Rab5- and Rab7-postive endosomes. These results indicated that, after internalization, ZIKV likely moves to Rab5-positive early endosome and Rab7-positive late endosomes before delivering its RNA into the cytoplasm. Taken together, our study, for the first time, described the early infection events of ZIKV in human glioblastoma cell T98G

Continuously Tunable 250 GHz Gyrotron with a Double Disk Window for DNP-NMR Spectroscopy

In this paper, we describe the design and experimental results from the rebuild of a 250 GHz gyrotron used for Dynamic Nuclear Polarization enhanced Nuclear Magnetic Resonance spectroscopy on a 380 MHz spectrometer. Tuning bandwidth of approximately 2 GHz is easily achieved at a fixed magnetic field of 9.24 T and a beam current of 95 mA producing an average output power of >10 W over the entire tuning band. This tube incorporates a double disk output sapphire window in order to maximize the transmission at 250.58 GHz. DNP Signal enhancement of >125 is achieved on a [superscript 13]C-Urea sample using this gyrotron.National Institutes of Health (U.S.) (Grant EB002804)National Institutes of Health (U.S.) (Grant EB003151)National Institutes of Health (U.S.) (Grant EB002026)National Institutes of Health (U.S.) (Grant EB001960)National Institutes of Health (U.S.) (Grant EB001035)National Institutes of Health (U.S.) (Grant EB001965)National Institutes of Health (U.S.) (Grant EB004866

Customer lifetime value: the effect of relational benefits, brand experiences, quality, satisfaction, trust and commitment in the fast-food restaurants

Purpose This study examines factors that affect customer lifetime value (CLV) in fast-food restaurants (FFRs) in Jordan. These factors are relational benefits, brand experiences, service quality (SQ), satisfaction, trust and commitment. Design/methodology/approach An online survey was collected from a sample of 503 respondents. The authors used SPSS to test the constructs' relationships and analyse the data. SmartPLS was used to test the hypotheses. Findings In contrast to previous studies, not all dimensions of brand experiences and relational benefits had a significant and positive influence on relationship marketing outcomes (satisfaction, trust and commitment). On the other hand, results demonstrated that SQ had a significant and positive influence on relationship marketing outcomes. Furthermore, research reveals that satisfaction, trust and commitment significantly and positively influenced CLV. Practical implications Those FFRs that seek to enhance CLV should build solid and sustainable bonds with their customers. This paper concludes by stating its implications, its limitations and the opportunities available for future research. Originality/value This study, which is unique in the Middle East, includes essential strategies for managing customer relationship that can be universally applied to improve customer benefits and maximise the performance of businesses

The influence of procedural volume and proficiency gain on mortality from upper GI endoscopic mucosal resection

OBJECTIVE: Endoscopic mucosal resection (EMR) is established for the management of benign and early malignant upper GI disease. The aim of this observational study was to establish the effect of endoscopist procedural volume on mortality. DESIGN: Patients undergoing upper GI EMR between 1997 and 2012 were identified from the Hospital Episode Statistics database. The primary outcome was 30-day mortality and secondary outcomes were 90-day mortality, requirement for emergency intervention and elective cancer re-intervention. Risk-adjusted cumulative sum (RA-CUSUM) analysis was used to assess patient mortality risk during initial stage of endoscopist proficiency gain and the effect of endoscopist and hospital volume. Mortality was compared before and after the change point or threshold in the RA-CUSUM curve. RESULTS: 11 051 patients underwent upper GI EMR. Endoscopist procedure volume was an independent predictor of 30-day mortality. Fifty-eight per cent of EMR procedures were performed by endoscopists with annual volume of 2 cases or less, and had a higher 30-day and 90-day mortality rate for patients with cancer, 6.1% vs 0.4% (p<0.001) and 12% vs 2.1% (p<0.001), respectively. The requirement for emergency intervention after EMR for cancer was also greater with low volume endoscopists (1.8% vs 0.1%, p=0.002). In patients with cancer, the RA-CUSUM curve change points for 30-day mortality and elective re-intervention were 4 cases and 43 cases, respectively. CONCLUSIONS: EMR performed by high volume endoscopists is associated with reduced adverse outcomes. In order to reach proficiency, appropriate training and procedural volume accreditation training programmes are needed nationally

The role of TG2 in regulating S100A4-mediated mammary tumour cell migration

The importance of S100A4, a Ca2+-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2) a Ca2+-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector) and highly metastatic KP1 cells (R37 cells transfected with S100A4), we demonstrate that inhibition of TG2 either by TG2 inhibitors or transfection of cells with TG2 shRNA block S100A4-accelerated cell migration in the KP1cells and in R37 cells treated with exogenous S100A4. Cell migration was also blocked by the treatment with the non-cell permeabilizing TG2 inhibitor R294, in the human breast cancer cell line MDA-MB-231 (Clone 16, which has a high level of TG2 expression). Inhibition was paralleled by a decrease in S100A4 polymer formation. co-immunoprecipitation and Far Western blotting assays and cross-linking assays showed not only the direct interaction between TG2 and S100A4, but also confirmed S100A4 as a substrate for TG2. Using specific functional blocking antibodies, a targeting peptide and a recombinant protein as a competitive treatment, we revealed the involvement of syndecan-4 and a5ß1 integrin co-signalling pathways linked by activation of PKCa in this TG2 and S100A4-mediated cell migration. We propose a mechanism for TG2-regulated S100A4-related mediated cell migration, which is dependent on TG2 crosslinking

Exploiting stochastic dominance to generate abnormal stock returns

We construct zero cost portfolios based on second and third degree stochastic dominance and show that they produce systematic, statistically significant, abnormal returns. These returns are robust with respect to the single index CAPM, the Fama-French 3-factor model, the Carhart 4-factor model and the liquidity 5-factor model. They are also robust with respect to momentum portfolios, transactions costs, varying time periods and when broken down by a range of risk factors, such as firm size, leverage, age, return volatility, cash flow volatility and trading volume

Hospital-presenting self-harm among older adults living in Ireland: a 13-year trend analysis from the National Self-Harm Registry Ireland.

To examine trends in rates of self-harm among emergency department (ED) presenting older adults in Ireland over a 13-year period. Population-based study using data from the National Self-Harm Registry Ireland. National hospital EDs. Older adults aged 60 years and over presenting with self-harm to hospital EDs in Ireland between January 1, 2007 and December 31, 2019. ED self-harm presentations. Between 2007 and 2019, there were 6931 presentations of self-harm in older adults. The average annual self-harm rate was 57.8 per 100,000 among older adults aged 60 years and over. Female rates were 1.1 times higher compared to their male counterparts (61.4 vs 53.9 per 100,000). Throughout the study time frame, females aged 60-69 years had the highest rates (88.1 per 100,000), while females aged 80 years and over had the lowest rates (18.7 per 100,000). Intentional drug overdose was the most commonly used method (75.5%), and alcohol was involved in 30.3% of presentations. Between the austerity and recession years (2007-2012), self-harm presentations were 7% higher compared to 2013-2019 (incidence rate ratio (IRR): 1.07 95% CI 1.02-1.13, = 0.01). Findings indicate that self-harm in older adults remains a concern with approximately 533 presentations per year in Ireland. While in younger age groups, females report higher rates of self-harm, this gender difference was reversed in the oldest age group (80 years and over), with higher rates of self-harm among males. Austerity/recession years (2007-2012) had significantly higher rates of self-harm compared to subsequent years

Spinor Bose-Einstein condensates

An overview on the physics of spinor and dipolar Bose-Einstein condensates (BECs) is given. Mean-field ground states, Bogoliubov spectra, and many-body ground and excited states of spinor BECs are discussed. Properties of spin-polarized dipolar BECs and those of spinor-dipolar BECs are reviewed. Some of the unique features of the vortices in spinor BECs such as fractional vortices and non-Abelian vortices are delineated. The symmetry of the order parameter is classified using group theory, and various topological excitations are investigated based on homotopy theory. Some of the more recent developments in a spinor BEC are discussed.Comment: To appear in Physics Reports. The PDF file with high resolution figures is available from the following website: http://cat.phys.s.u-tokyo.ac.jp/publication/review_of_spinorBEC.pd

Metabolomic Profiling of Drug Responses in Acute Myeloid Leukaemia Cell Lines

Combined bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) exert unexpected antileukaemic activities against acute myeloid leukaemia (AML) and these activities are associated with the generation of reactive oxygen species (ROS) within the tumor cells. Although the generation of ROS by these drugs is supported by preceding studies including our own, the interrelationship between the cellular effects of the drugs and ROS generation is not well understood. Here we report the use of NMR metabolomic profiling to further study the effect of BEZ and MPA on three AML cell lines and to shed light on the underlying mechanism of action. For this we focused on drug effects induced during the initial 24 hours of treatment prior to the onset of overt cellular responses and examined these in the context of basal differences in metabolic profiles between the cell lines. Despite their ultimately profound cellular effects, the early changes in metabolic profiles engendered by these drugs were less pronounced than the constitutive metabolic differences between cell types. Nonetheless, drug treatments engendered common metabolic changes, most markedly in the response to the combination of BEZ and MPA. These responses included changes to TCA cycle intermediates consistent with recently identified chemical actions of ROS. Notable amongst these was the conversion of α-ketoglutarate to succinate which was recapitulated by the treatment of cell extracts with exogenous hydrogen peroxide. These findings indicate that the actions of combined BEZ and MPA against AML cells are indeed mediated downstream of the generation of ROS rather than some hitherto unsuspected mechanism. Moreover, our findings demonstrate that metabolite profiles represent highly sensitive markers for genomic differences between cells and their responses to external stimuli. This opens new perspectives to use metabolic profiling as a tool to study the rational redeployment of drugs in new disease settings