The quantum nature of the electromagnetic field imposes a fundamental limit on the sensitivity of optical precision measurements such as spectroscopy, microscopy and interferometry. The so-called ...quantum limit is set by the zero-point fluctuations of the electromagnetic field, which constrain the precision with which optical signals can be measured. In the world of precision measurement, laser-interferometric gravitational-wave detectors are the most sensitive position meters ever operated, capable of measuring distance changes of the order of 10−18 m r.m.s. over kilometre separations caused by gravitational waves from astronomical sources. The sensitivity of currently operational and future gravitational-wave detectors is limited by quantum optical noise. Here, we demonstrate a 44% improvement in displacement sensitivity of a prototype gravitational-wave detector with suspended quasi-free mirrors at frequencies where the sensitivity is shot-noise-limited, by injecting a squeezed state of light. This demonstration is a critical step towards implementation of squeezing-enhancement in large-scale gravitational-wave detectors.
Mitral regurgitation (MR) and microvascular obstruction (MVO) are common complications of myocardial infarction (MI). This study aimed to investigate the association between MR in ST-elevation MI ...(STEMI) subjects with MVO post-reperfusion. STEMI subjects undergoing primary percutaneous intervention were enrolled. Cardiovascular magnetic resonance (CMR) imaging was performed within 48-hours of initial presentation. 4D flow images of CMR were analysed using a retrospective valve tracking technique to quantify MR volume, and late gadolinium enhancement images of CMR to assess MVO.
Among 69 patients in the study cohort, 41 had MVO (59%). Patients with MVO had lower left ventricular (LV) ejection fraction (EF) (42 ± 10% vs. 52 ± 8%, P < 0.01), higher end-systolic volume (98 ± 49 ml vs. 73 ± 28 ml, P < 0.001) and larger scar volume (26 ± 19% vs. 11 ± 9%, P < 0.001). Extent of MVO was associated with the degree of MR quantified by 4D flow (R = 0.54, P = 0.0003). In uni-variate regression analysis, investigating the association of CMR variables to the degree of acute MR, only the extent of MVO was associated (coefficient = 0.27, P = 0.001). The area under the curve for the presence of MVO was 0.66 (P = 0.01) for MR > 2.5 ml. We conclude that in patients with reperfused STEMI, the degree of acute MR is associated with the degree of MVO.
Background: Although low dietary intakes of antioxidant vitamins and minerals have been associated with higher risks of cancer, results of trials testing antioxidant supplementation for cancer ...chemoprevention have been equivocal. We assessed whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer. Methods: We conducted a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between October 1, 1994, and June 6, 2000. Supplementation with α-tocopherol (400 IU/day) and β-carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. In the course of the trial, β-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received α-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving α-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with α-tocopherol. The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms. Conclusions: α-Tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.
Transient early-life perturbations in glucocorticoids (GC) are linked with cardiovascular disease risk in later life. Here the impact of early life manipulations of GC on adult heart structure, ...function and gene expression were assessed.
Zebrafish embryos were incubated in dexamethasone (Dex) or injected with targeted glucocorticoid receptor (GR) morpholino knockdown (GR Mo) over the first 120 h post fertilisation (hpf); surviving embryos (>90%) were maintained until adulthood under normal conditions. Cardiac function, heart histology and cardiac genes were assessed in embryonic (120 hpf) and adult (120 days post fertilisation (dpf)) hearts.
GR Mo embryos (120 hpf) had smaller hearts with fewer cardiomyocytes, less mature striation pattern, reduced cardiac function and reduced levels of vmhc and igf mRNA compared with controls. GR Mo adult hearts were smaller with diminished trabecular network pattern, reduced expression of vmhc and altered echocardiographic Doppler flow compared to controls. Dex embryos had larger hearts at 120 hpf (Dex 107.2 ± 3.1 vs. controls 90.2 ± 1.1 μm, p < 0.001) with a more mature trabecular network and larger cardiomyocytes (1.62 ± 0.13 cells/μm vs control 2.18 ± 0.13 cells/μm, p < 0.05) and enhanced cardiac performance compared to controls. Adult hearts were larger (1.02 ± 0.07 μg/mg vs controls 0.63 ± 0.06 μg/mg, p = 0.0007), had increased vmhc and gr mRNA levels.
Perturbations in GR activity during embryonic development results in short and long-term alterations in the heart.
•Embryonic glucocorticoid exposure can have direct impact on cardiac development.•Altered glucocorticoid activity change the developing heart structure and function.•Changes in structure, function and gene expression are also observed in later life.•These subtle changes in the adult heart may increase the risk of disorder or dysfunction.
Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its ...conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas the local spread of activated metabolites can kill nearby cells lacking the enzyme (bystander cell killing). One promising combination that has entered clinical trials uses the nitroreductase NfsB from Escherichia coli to activate the prodrug, CB1954, to a potent bifunctional alkylating agent. NfsA, the major E. coli nitroreductase, has greater activity with nitrofuran antibiotics, but it has not been compared in the past with NfsB for the activation of CB1954. We show superior in vitro kinetics of CB1954 activation by NfsA using the NADPH cofactor, and show that the expression of NfsA in bacterial or human cells results in a 3.5- to 8-fold greater sensitivity to CB1954, relative to NfsB. Although NfsB reduces either the 2-NO(2) or 4-NO(2) positions of CB1954 in an equimolar ratio, we show that NfsA preferentially reduces the 2-NO(2) group, which leads to a greater bystander effect with cells expressing NfsA than with NfsB. NfsA is also more effective than NfsB for cell sensitisation to nitrofurans and to a selection of alternative, dinitrobenzamide mustard (DNBM) prodrugs.
Background: The coordination of cell cycle events is necessary to ensure the proper duplication and dissemination of the genome. In this study, we examine the consequences of depleting Drad21 and SA, ...two non-SMC subunits of the cohesin complex, by dsRNA-mediated interference in Drosophila cultured cells.
Results: We have shown that a bona fide cohesin complex exists in Drosophila embryos. Strikingly, the Drad21/Scc1 and SA/Scc3 non-SMC subunits associate more intimately with one another than they do with the SMCs. We have observed defects in mitotic progression in cells from which Drad21 has been depleted: cells delay in prometaphase with normally condensed, but prematurely separated, sister chromatids and with abnormal spindle morphology. Much milder defects are observed when SA is depleted from cells. The dynamics of the chromosome passenger protein, INCENP, are affected after Drad21 depletion. We have also made the surprising observation that SA is unstable in the absence of Drad21; however, we have shown that the converse is not true. Interference with Drad21 in living Drosophila embryos also has deleterious effects on mitotic progression.
Conclusions: We conclude that Drad21, as a member of a cohesin complex, is required in Drosophila cultured cells and embryos for proper mitotic progression. The protein is required in cultured cells for chromosome cohesion, spindle morphology, dynamics of a chromosome passenger protein, and stability of the cohesin complex, but apparently not for normal chromosome condensation. The observation of SA instability in the absence of Drad21 implies that the expression of cohesin subunits and assembly of the cohesin complex will be tightly regulated.
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