Simulation of superresolution holography for optical tweezers

Optical tweezers manipulate microscopic particles using foci of light beams. Their performance is therefore limited by diffraction. Using computer simulations of a model system, we investigate the application of superresolution holography for two-dimensional (2D) light shaping in optical tweezers, which can beat the diffraction limit. We use the direct-search and Gerchberg algorithms to shape the center of a light beam into one or two bright spots; we do not constrain the remainder of the beam. We demonstrate that superresolution algorithms can significantly improve the normalized stiffness of an optical trap and the minimum separation at which neighboring traps can be resolved. We also test if such algorithms can be used interactively, as is desirable in optical tweezers

Visible photodissociation spectroscopy of PAH cations and derivatives in the PIRENEA experiment

The electronic spectra of gas-phase cationic polycyclic aromatic hydrocarbons (PAHs), trapped in the Fourier Transform Ion Cyclotron Resonance cell of the PIRENEA experiment, have been measured by multiphoton dissociation spectroscopy in the 430-480 nm spectral range using the radiation of a mid-band optical parametric oscillator laser. We present here the spectra recorded for different species of increasing size, namely the pyrene cation (C16H10+), the 1-methylpyrene cation (CH3-C16H9+), the coronene cation (C24H12+), and its dehydrogenated derivative C24H10+. The experimental results are interpreted with the help of time-dependent density functional theory calculations and analysed using spectral information on the same species obtained from matrix isolation spectroscopy data. A kinetic Monte Carlo code has also been used, in the case of pyrene and coronene cations, to estimate the absorption cross-sections of the measured electronic transitions. Gas-phase spectra of highly reactive species such as dehydrogenated PAH cations are reported for the first time

Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: Report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group

Poor inclusion rates into clinical trials for teenagers and young adults (TYA; aged 13–24 years) have been assumed but not systematically investigated in England. We analysed accrual rates (AR) from 1 April 2005 up to 31 March 2007 to National Cancer Research Network (NCRN) Phase III trials for the commonest tumour types occurring in TYA and children: leukaemia, lymphoma, brain and central nervous system, bone sarcomas and male germ cell tumours. AR for 2005–2007 were 43.2% for patients aged 10–14 years, 25.2% for patients aged 15–19 years, and 13.1% for patients aged 20–24 years in the tumour types analysed. Compared with accrual from 1 April 2005 to 31 March 2006, AR between 1 April 2006 and 31 March 2007 increased for those aged 10–14 and 15–19 years, but fell for those aged 20–24 years. AR varied considerably among cancer types. Despite four trials being available, patients over 16 years with central nervous system tumours were not recruited. Rates of participation in clinical trials in England from 2005 to 2007 were much lower for TYA older than 15 years compared with children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. Other possible influences, such as difficulties associated with the consent of TYA require further evaluation. Closer dialogue between those involved in planning and running trials for children and for adults is necessary to improve trial availability and recruitment. Further research is required to identify trends in trial availability and accrual for those tumours constituting the remaining 26% of TYA cancers

Symptomatic relief precedes improvement of myocardial blood flow in patients under spinal cord stimulation

BACKGROUND: Spinal cord electrical stimulation (SCS) has shown to be a treatment option for patients suffering from angina pectoris CCS III-IV although being on optimal medication and not suitable for conventional treatment strategies, e.g. CABG or PTCA. Although many studies demonstrated a clear symptomatic relief under SCS therapy, there are only a few short-term studies that investigated alterations in cardiac ischemia. Therefore doubts remain whether SCS has a direct effect on myocardial perfusion. METHODS: A prospective study to investigate the short- and long-term effect of spinal cord stimulation (SCS) on myocardial ischemia in patients with refractory angina pectoris and coronary multivessel disease was designed. Myocardial ischemia was measured by MIBI-SPECT scintigraphy 3 months and 12 months after the beginning of neurostimulation. To further examine the relation between cardiac perfusion and functional status of the patients we measured exercise capacity (bicycle ergometry and 6-minute walk test), symptoms and quality of life (Seattle Angina Questionnaire [SAQ]), as well. RESULTS: 31 patients (65 ± 11 SEM years; 25 male, 6 female) were included into the study. The average consumption of short acting nitrates (SAN) decreased rapidly from 12 ± 1.6 times to 3 ± 1 times per week. The walking distance and the maximum workload increased from 143 ± 22 to 225 ± 24 meters and 68 ± 7 to 96 ± 12 watt after 3 months. Quality of life increased (SAQ) significantly after 3 month compared to baseline, as well. No further improvement was observed after one year of treament. Despite the symptomatic relief and the improvement in maximal workload computer based analysis (Emory Cardiac Toolbox) of the MIBI-SPECT studies after 3 months of treatment did not show significant alterations of myocardial ischemia compared to baseline (16 patients idem, 7 with increase and 6 with decrease of ischemia, 2 patients dropped out during initial test phase). Interestingly, in the long-term follow up after one year 16 patients (of 27 who completed the one year follow up) showed a clear decrease of myocardial ischemia and only one patient still had an increase of ischemia compared to baseline. CONCLUSION: Thus, spinal cord stimulation not only relieves symptoms, but reduces myocardial ischemia as well. However, since improvement in symptoms and exercise capacity starts much earlier, decreased myocardial ischemia might not be a direct effect of neurostimulation but rather be due to a better coronary collateralisation because of an enhanced physical activity of the patients

FTO influences adipogenesis by regulating mitotic clonal expansion

The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Cannabinoid Regulation of Nitric Oxide Synthase I (nNOS) in Neuronal Cells

In our previous studies, CB1 cannabinoid receptor agonists stimulated production of cyclic GMP and translocation of nitric oxide (NO)-sensitive guanylyl cyclase in neuronal cells (Jones et al., Neuropharmacology 54:23–30, 2008). The purpose of these studies was to elucidate the signal transduction of cannabinoid-mediated neuronal nitric oxide synthase (nNOS) activation in neuronal cells. Cannabinoid agonists CP55940 (2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), and the metabolically stable analog of anandamide, (R)-(+)-methanandamide stimulated NO production in N18TG2 cells over a 20-min period. Rimonabant (N-(piperidin-lyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-pyrazole-3-carboxamide), a CB1 receptor antagonist, partially or completely curtailed cannabinoid-mediated NO production. Inhibition of NOS activity (NG-nitro-l-arginine) or signaling via Gi/o protein (pertussis toxin) significantly limited NO production by cannabinoid agonists. Ca2+ mobilization was not detected in N18TG2 cells after cannabinoid treatment using Fluo-4 AM fluorescence. Cannabinoid-mediated NO production was attributed to nNOS activation since endothelial NOS and inducible NOS protein and mRNA were not detected in N18TG2 cells. Bands of 160 and 155 kDa were detected on Western blot analysis of cytosolic and membrane fractions of N18TG2 cells, using a nNOS antibody. Chronic treatment of N18TG2 cells with cannabinoid agonists downregulated nNOS protein and mRNA as detected using Western blot analysis and real-time polymerase chain reaction, respectively. Cannabinoid agonists stimulated NO production via signaling through CB1 receptors, leading to activation of Gi/o protein and enhanced nNOS activity. The findings of these studies provide information related to cannabinoid-mediated NO signal transduction in neuronal cells, which has important implications in the ongoing elucidation of the endocannabinoid system in the nervous system

Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.

Constraints on Charon's Orbital Elements from the Double Stellar Occultation of 2008 June 22

The original publication is available at http://iopscience.iop.org/1538-3881/International audiencePluto and its main satellite, Charon, occulted the same star on 2008 June 22. This event was observed from Australia and La Réunion Island, providing the east and north Charon Plutocentric offset in the sky plane (J2000): X= + 12,070.5 ± 4 km (+ 546.2 ± 0.2 mas), Y= + 4,576.3 ± 24 km (+ 207.1 ± 1.1 mas) at 19:20:33.82 UT on Earth, corresponding to JD 2454640.129964 at Pluto. This yields Charon's true longitude L= 153.483 ± 0fdg071 in the satellite orbital plane (counted from the ascending node on J2000 mean equator) and orbital radius r= 19,564 ± 14 km at that time. We compare this position to that predicted by (1) the orbital solution of Tholen & Buie (the "TB97" solution), (2) the PLU017 Charon ephemeris, and (3) the solution of Tholen et al. (the "T08" solution). We conclude that (1) our result rules out solution TB97, (2) our position agrees with PLU017, with differences of ΔL= + 0.073 ± 0fdg071 in longitude, and Δr= + 0.6 ± 14 km in radius, and (3) while the difference with the T08 ephemeris amounts to only ΔL= 0.033 ± 0fdg071 in longitude, it exhibits a significant radial discrepancy of Δr= 61.3 ± 14 km. We discuss this difference in terms of a possible image scale relative error of 3.35 × 10-3in the 2002-2003 Hubble Space Telescope images upon which the T08 solution is mostly based. Rescaling the T08 Charon semi-major axis, a = 19, 570.45 km, to the TB97 value, a = 19636 km, all other orbital elements remaining the same ("T08/TB97" solution), we reconcile our position with the re-scaled solution by better than 12 km (or 0.55 mas) for Charon's position in its orbital plane, thus making T08/TB97 our preferred solution