Universal quantum logic in hot silicon qubits.

Quantum computation requires many qubits that can be coherently controlled and coupled to each other1. Qubits that are defined using lithographic techniques have been suggested to enable the development of scalable quantum systems because they can be implemented using semiconductor fabrication technology2-5. However, leading solid-state approaches function only at temperatures below 100 millikelvin, where cooling power is extremely limited, and this severely affects the prospects of practical quantum computation. Recent studies of electron spins in silicon have made progress towards a platform that can be operated at higher temperatures by demonstrating long spin lifetimes6, gate-based spin readout7 and coherent single-spin control8. However, a high-temperature two-qubit logic gate has not yet been demonstrated. Here we show that silicon quantum dots can have sufficient thermal robustness to enable the execution of a universal gate set at temperatures greater than one kelvin. We obtain single-qubit control via electron spin resonance and readout using Pauli spin blockade. In addition, we show individual coherent control of two qubits and measure single-qubit fidelities of up to 99.3 per cent. We demonstrate the tunability of the exchange interaction between the two spins from 0.5 to 18 megahertz and use it to execute coherent two-qubit controlled rotations. The demonstration of 'hot' and universal quantum logic in a semiconductor platform paves the way for quantum integrated circuits that host both the quantum hardware and its control circuitry on the same chip, providing a scalable approach towards practical quantum information processing.

A programmable two-qubit quantum processor in silicon.

Now that it is possible to achieve measurement and control fidelities for individual quantum bits (qubits) above the threshold for fault tolerance, attention is moving towards the difficult task of scaling up the number of physical qubits to the large numbers that are needed for fault-tolerant quantum computing. In this context, quantum-dot-based spin qubits could have substantial advantages over other types of qubit owing to their potential for all-electrical operation and ability to be integrated at high density onto an industrial platform. Initialization, readout and single- and two-qubit gates have been demonstrated in various quantum-dot-based qubit representations. However, as seen with small-scale demonstrations of quantum computers using other types of qubit, combining these elements leads to challenges related to qubit crosstalk, state leakage, calibration and control hardware. Here we overcome these challenges by using carefully designed control techniques to demonstrate a programmable two-qubit quantum processor in a silicon device that can perform the Deutsch-Josza algorithm and the Grover search algorithm-canonical examples of quantum algorithms that outperform their classical analogues. We characterize the entanglement in our processor by using quantum-state tomography of Bell states, measuring state fidelities of 85-89 per cent and concurrences of 73-82 per cent. These results pave the way for larger-scale quantum computers that use spins confined to quantum dots.

CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study.

PURPOSE: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. METHODS: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). RESULTS: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00-2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). CONCLUSIONS: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects.

BACKGROUND: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. METHODS: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. RESULTS: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ≥20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. CONCLUSION: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.

Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation.

BACKGROUND: Beyond estrogen receptor (ER), there are no validated predictors for tamoxifen (TAM) efficacy and toxicity. We utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular sensitivity to TAM. DESIGN: Our discovery model incorporates multidimensional datasets, including genome-wide genotype, gene expression, and endoxifen-induced cellular growth inhibition in the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide findings were further evaluated in NCI60 cancer cell lines. Gene knock-down experiments were performed in four breast cancer cell lines. Genetic variants identified in the cell-based model were examined in 245 Caucasian breast cancer patients who underwent TAM treatment. RESULTS: We identified seven novel single-nucleotide polymorphisms (SNPs) associated with endoxifen sensitivity through the expression of 10 genes using the genome-wide integrative analysis. All 10 genes identified in LCLs were associated with TAM sensitivity in NCI60 cancer cell lines, including USP7. USP7 knock-down resulted in increasing resistance to TAM in four breast cancer cell lines tested, which is consistent with the finding in LCLs and in the NCI60 cells. Furthermore, we identified SNPs that were associated with TAM-induced toxicities in breast cancer patients, after adjusting for other clinical factors. CONCLUSION: Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.

Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy.

BACKGROUND: Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone. METHODS: A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months. RESULTS: The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected. CONCLUSION: The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.

Facts, noise and wishful thinking: muscle protein turnover in aging and human disuse atrophy.

Surprisingly little is known about the mechanisms of muscle atrophy with aging and disuse in human beings, in contrast to rodents, from which much has been extrapolated to explain the human condition. However, this extrapolation is likely unwarranted because the time course, extent of wasting, muscle fiber involvement and alterations of muscle protein turnover are all quite different in rodent and human muscle. Furthermore, there is little evidence that static indices of protein turnover represent dynamic changes and may be misleading. With disuse there are reductions in the rate of muscle protein synthesis (MPS) large enough to explain the atrophic loss of muscle protein without a concomitant increase in proteolysis. In aging, there is no evidence that there are marked alterations in basal muscle protein turnover in healthy individuals but instead the ability to maintain muscle after feeding is compromised. This anabolic resistance is evident with physical inactivity, which exacerbates the inability to maintain muscle mass with aging. The main conclusion of this review is that in uncomplicated, non-inflammatory disuse atrophy, the facilitative change causing loss of muscle mass is a depression of MPS, exacerbated by anabolic resistance during feeding, with possible adaptive depressions, rather than increases, of muscle proteolysis.

The on-line characterization of a radium slurry by gamma-ray spectrometry.

We have developed an in-line monitor to directly measure the (226)Ra concentration in a nuclear waste stream using quantitative gamma-ray spectrometry applied to the 186keV emission. The waste stream is in the form of a slurry composed of the solid waste material mixed with water. The concentration measurement includes a self-attenuation correction factor determined from a transmission measurement using the 122keV gamma from (57)Co. Presented here is the model for the measurement system and results from some initial tests.

Uncertainty in rate loss corrections based on counting a periodic pulser.

Tomographic gamma scanning of waste produces three-dimensional transmission and emission images. These are used to derive item-specific attenuation correction factors that improve the accuracy of non-destructive waste assay. For each vertical layer, data grabs of short duration are acquired as the waste item is rotated and translated. The image reconstruction demands accurate rate loss corrections to minimize assay bias. For this application a pulser was used to perform the necessary rate loss corrections. In this work, we summarize the benefits of the pulser approach and review the basic principles on which the method is based. We extend the treatment to include a derivation of the expression for the uncertainty in the net pulser peak area in the presence of an underlying continuum. We report experimental results, taken using a Canberra model WM2900 Tomographic Gamma Scanner, over a broad range of count-rates and peak-to-continuum ratios. Repeat counts under controlled conditions allowed the correction factor and its variance to be determined and compared against expectations. These results confirm the validity of the correction factor formula and the corresponding expression for its uncertainty. The rate loss analysis has been built into a Monte Carlo Replicate engine to allow the uncertainty to be propagated into the total measurement uncertainty of the final assay.

Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver.

Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.

A randomized control trial of a psychosocial intervention for caregivers of allogeneic hematopoietic stem cell transplant patients: effects on distress.

Caregivers of patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT) serve a pivotal role in patient care but experience high stress, anxiety and depression as a result. We theorized that stress management adapted for allo-HSCT caregivers would reduce distress compared with treatment as usual (TAU). Of 267 consecutive caregivers of allo-HSCT patients approached, 148 (mean=53.5 years, 75.7% female) were randomized to either psychosocial intervention (i=74) or TAU (n=74). Eight one-on-one stress management sessions delivered across the 100-day post-transplant period focused on understanding stress, changing role(s) as caregiver, cognitive behavioral stress management, pacing respiration and identifying social support. Primary outcomes included perceived stress (psychological) and salivary cortisol awakening response (CAR) (physiological). Randomized groups were not statistically different at baseline. Mixed models analysis of covariance (intent-to-treat) showed that intervention was associated with significantly lower caregiver stress 3 months post transplant (mean=20.0, 95% confidence interval (95% CI)=17.9-22.0) compared with TAU (mean=23.0, 95% CI=21.0-25.0) with an effect size (ES) of 0.39 (P=0.039). Secondary psychological outcomes, including depression and anxiety, were significantly reduced with ESs of 0.46 and 0.66, respectively. Caregiver CAR did not differ from non-caregiving controls at baseline and was unchanged by intervention. Despite significant caregiving burden, this psychosocial intervention significantly mitigated distress in allo-HSCT caregivers.

Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain.

Postmortem human brains have been obtained from four nonpsychiatric patients, aged 59-70 years. Regional analysis of the trace amines phenylethylamine, p-tyramine, m-tyramine, and tryptamine has indicated that the amines are distributed heterogeneously throughout the brain, but are most concentrated in the basal ganglia. Although the levels are very low, evidence obtained from animal studies has indicated that the trace amines have a very rapid turnover rate. Their presence in a brain synaptosomal fraction suggests a possible involvement in the process of neurotransmission. Postmortem changes in human brain amines are discussed in relation to those occurring postmortem in the rat brain, in which phenylethylamine, p-tyramine, and tryptamine have been shown to increase to levels greater than those prevailing in vivo.

In vivo release of endogenous dopamine from rat caudate nucleus by phenylethylamine.

The in vivo release of endogenous dopamine (DA) from the rat caudate nucleus has been measured in the presence and absence of beta-phenylethylamine. A push-pull cannula was implanted into the brain and the tissue was perfused with artificial cerebrospinal fluid (CSF) containing phenylethylamine in concentrations ranging from 5 X 10(-3) to 5 X 10(-7) M. The DA released into the perfusate was determined radioenzymatically. Dopamine was released at rates significantly greater than its resting rate by concentrations of phenylethylamine of 5 X 10(-3) to 5 X 10(-5)M; 5 X 10(-6)M phenylethylamine caused a slight increase in release, but the difference from the resting rate was not significant. The absence of calcium in the perfusing medium did not significantly alter either the unstimulated release rate of DA or the release rate stimulated by 5 X 10(-5)M phenylethylamine. The concentrations of phenylethylamine required to increase release of DA in vivo are discussed briefly in relation to the doses required to elicit behavioural effects.

The measurement of blood pressure: sitting or supine, once or twice?

In 166 patients attending a hypertension review clinic, we compared supine and sitting blood pressure measurements and first and second measurements (1 min apart) in each position to determine whether any differences seen might have implications for the routine measurement of blood pressure in these patients, as a group or as individuals. Measurements were made with the Copal UA-251 semi-automated sphygmomanometer. In the group there was no significant difference between the first and the second diastolic measurements. The first systolic measurement was on average 3-4 mmHg higher than the second in both positions. Mean supine systolic pressures were 2-3 mmHg higher and diastolic pressures 2-3 mmHg lower than the corresponding sitting pressures. In individual subjects there were substantial disagreements between successive measurements in both positions and between positions. However, these differences would not have influenced blood pressure management in more than a few instances. We suggest that two measurements should routinely be taken, and the average recorded, particularly when the average exceeds 155/90 mmHg.

The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain.

1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.

Infant immune response to human rotavirus serotype G1 vaccine candidate reassortant WI79-9: different dose response patterns to virus surface proteins VP7 and VP4.

BACKGROUND: Rotavirus is the leading cause of morbidity from gastroenteritis in the developed world and the leading cause of mortality from viral gastroenteritis (estimated 600000 deaths) worldwide. G1 is the most prevalent human serotype. Reassortant rotavirus between simian rotavirus RRV or bovine rotavirus WC3 and human strain rotaviruses have been extensively tested as candidate vaccines. Rotavirus (RV) reassortant strain WI79-9 consists of a human (strain WI79) G1 serotype VP7 surface protein on a bovine (strain WC3) background. It is a key component of a pentavalent (G1, G2, G3, G4 and P1) WC3 reassortant vaccine candidate, RotaTeq, now being tested in Phase III clinical trials. METHODS: We studied 84 infants between the ages of 2 and 8 months who received 3 oral doses of WI79-9. Serum neutralizing antibody was measured to the human (WI79 serotype P1 G1) and bovine (WC3 serotype P7 G6) parent RV after each dose. A significant response was defined as a > or =3-fold rise in antibody titer between the predose and postdose sera. RESULTS: In two separate cohorts of vaccinees given three doses of WI79-9 reassortant rotavirus, 68 to 75% of infants demonstrated a significant response to WC3 (VP4, P7) after Dose 1, fewer (24 to 39%) responses were detected after Dose 2 and rare (0 to 4%) additional responses occurred after Dose 3. The cumulative response rate to WC3 after three doses was 95% in both trials. In contrast 23 to 37% had a significant response to WI79 (VP7, G1) after Dose 1, and 57 to 61% had a significant response after Dose 2. Additional significant responses after Dose 3 led to a cumulative response of 70 to 84%. CONCLUSION: Two doses of G1 reassortant WI79 were necessary to induce significant antibody responses to human G1 (VP7) antigen in >50% of infants. Three doses were required to achieve significant antibody responses to VP7 in >70% of infants.

Photoproduction of straight phi(1020) mesons on the proton at large momentum transfer

The cross section for straight phi meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the straight phi.

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat.

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 micrograms) or apomorphine (5, 10 and 20 micrograms) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.

In vivo release of endogenous dopamine from rat caudate putamen and nucleus accumbens by 40 mM potassium chloride.

The resting and K+-stimulated release rates of endogenous dopamine (DA) have been measured in vivo at four different sites in the rat caudate putamen and nucleus accumbens. A push-pull cannula was inserted into the brain sites chosen, and the tissue was perfused with artificial cerebrospinal fluid (CSF) containing 2.6 or 40 mM KC1. The DA content of the perfusates was determined by a radioenzymatic procedure. DA release was significantly increased above unstimulated levels by 40 mM KC1 in all areas tested. Neither unstimulated nor K+-stimulated release rates varied significantly among the regions examined. K+-stimulated DA release was not significantly diminished by perfusing the tissue with calcium-free medium, suggesting that release was probably supported by residual amounts of calcium in the tissue.

In vivo release of endogenous dopamine from rat caudate nucleus by beta-phenylethylamine and alpha,alpha,-dideutero-beta-phenylethylamine.

The release of endogenous dopamine (DA) has been measured in the rat striatum following the intracardial administration of various doses of beta-phenylethylamine (PEA) or alpha,alpha-dideutero-beta-phenylethylamine (deuterated PEA). The release was significantly increased for a period of approximately 15 minutes by a dose of 25 mg/kg PEA. Both the dose required to stimulate DA release and the duration of the effect were in good agreement with previously reported behavioral and locomotor effects of administered PEA. When the animals were given 25 mg/kg of deuterated PEA, the increase in DA release was both longer lasting and significantly greater in magnitude than that observed in response to the non-deuterated amine. The results of these experiments provide direct evidence that DA release is stimulated by amounts of PEA known to cause behavioral effects and locomotor activity in rats, and suggest that these effects are likely to be mediated, at least in part, by DA.