Radio frequency measurements of tunnel couplings and singlet–triplet spin states in Si:P quantum dots

Spin states of the electrons and nuclei of phosphorus donors in silicon are strong candidates for quantum information processing applications given their excellent coherence times. Designing a scalable donor-based quantum computer will require both knowledge of the relationship between device geometry and electron tunnel couplings, and a spin readout strategy that uses minimal physical space in the device. Here we use radio frequency reflectometry to measure singlet–triplet states of a few-donor Si:P double quantum dot and demonstrate that the exchange energy can be tuned by at least two orders of magnitude, from 20 μeV to 8 meV. We measure dot–lead tunnel rates by analysis of the reflected signal and show that they change from 100 MHz to 22 GHz as the number of electrons on a quantum dot is increased from 1 to 4. These techniques present an approach for characterizing, operating and engineering scalable qubit devices based on donors in silicon

Identification of a novel homozygous nonsense mutation in EYS in a Chinese family with autosomal recessive retinitis pigmentosa

<p>Abstract</p> <p>Background</p> <p>Retinitis pigmentosa is the most important hereditary retinal degenerative disease, which has a high degree of clinical and genetic heterogeneity. More than half of all cases of retinitis pigmentosa are autosomal recessive (arRP), but the gene(s) causing arRP in most families has yet to be identified. The purpose of this study is to identify the genetic basis of severe arRP in a consanguineous Chinese family.</p> <p>Methods</p> <p>Linkage and haplotype analyses were used to define the chromosomal location of the pathogenic gene in the Chinese arRP family. Direct DNA sequence analysis of the entire coding region and exon-intron boundaries of <it>EYS </it>was used to determine the disease-causing mutation, and to demonstrate that the mutation co-segregates with the disease in the family.</p> <p>Results</p> <p>A single nucleotide substitution of G to T at nucleotide 5506 of EYS was identified in the Chinese arRP family. This change caused a substitution of a glutamic acid residue at codon 1,836 by a stop codon TAA (p.E1836X), and resulted in a premature truncated EYS protein with 1,835 amino acids. Three affected siblings in the family were homozygous for the p.E1836X mutation, while the other unaffected family members carried one mutant allele and one normal EYS allele. The nonsense mutation p.E1836X was not detected in 200 unrelated normal controls.</p> <p>Conclusions</p> <p>The <it>EYS </it>gene is a recently identified disease-causing gene for retinitis pigmentosa, and encodes the orthologue of <it>Drosophila </it>spacemaker. To date, there are only eight mutations in <it>EYS </it>that have been identified to cause arRP. Here we report one novel homozygous nonsense mutation of <it>EYS </it>in a consanguineous Chinese arRP family. Our study represents the first independent confirmation that mutations in <it>EYS </it>cause arRP. Additionally, this is the first <it>EYS </it>mutation identified in the Chinese population.</p

Head Exposure to Cold during Whole-Body Cryostimulation: Influence on Thermal Response and Autonomic Modulation

Recent research on whole-body cryotherapy has hypothesized a major responsibility of head cooling in the physiological changes classically reported after a cryostimulation session. The aim of this experiment was to verify this hypothesis by studying the influence of exposing the head to cold during whole-body cryostimulation sessions, on the thermal response and the autonomic nervous system (ANS). Over five consecutive days, two groups of 10 participants performed one whole-body cryostimulation session daily, in one of two different systems; one exposing the whole-body to cold (whole-body cryostimulation, WBC), and the other exposing the whole-body except the head (partial-body cryostimulation, PBC).10 participants constituted a control group (CON) not receiving any cryostimulation. In order to isolate the head-cooling effect on recorded variables, it was ensured that the WBC and PBC systems induced the same decrease in skin temperature for all body regions (mean decrease over the 5 exposures: -8.6°C±1.3°C and -8.3±0.7°C for WBC and PBC, respectively), which persisted up to 20-min after the sessions (P20). The WBC sessions caused an almost certain decrease in tympanic temperature from Pre to P20 (-0.28 ±0.11°C), while it only decreased at P20 (-0.14±0.05°C) after PBC sessions. Heart rate almost certainly decreased after PBC (-8.6%) and WBC (-12.3%) sessions. Resting vagal-related heart rate variability indices (the root-mean square difference of successive normal R-R intervals, RMSSD, and high frequency band, HF) were very likely to almost certainly increased after PBC (RMSSD:+49.1%, HF: +123.3%) and WBC (RMSSD: +38.8%, HF:+70.3%). Plasma norepinephrine concentration was likely increased in similar proportions after PBC and WBC, but only after the first session. Both cryostimulation techniques stimulated the ANS with a predominance of parasympathetic tone activation from the first to the fifth session and in slightly greater proportion with WBC than PBC. The main result of this study indicates that the head exposure to cold during whole-body cryostimulation may not be the main factor responsible for the effects of cryostimulation on the ANS

Prevalence and progression of visual impairment in patients newly diagnosed with clinical type 2 diabetes: a 6-year follow up study

<p>Abstract</p> <p>Background</p> <p>Many diabetic patients fear visual loss as the worst consequence of diabetes. In most studies the main eye pathology is assigned as the cause of visual impairment. This study analysed a broad range of possible ocular and non-ocular predictors of visual impairment prospectively in patients newly diagnosed with clinical type 2 diabetes.</p> <p>Methods</p> <p>Data were from a population-based cohort of 1,241 persons newly diagnosed with clinical, often symptomatic type 2 diabetes aged ≥ 40 years. After 6 years, 807 patients were followed up. Standard eye examinations were done by practising ophthalmologists.</p> <p>Results</p> <p>At diabetes diagnosis median age was 65.5 years. Over 6 years, the prevalence of blindness (visual acuity of best seeing eye ≤ 0.1) rose from 0.9% (11/1,241) to 2.4% (19/807) and the prevalence of moderate visual impairment (> 0.1; < 0.5) rose from 5.4% (67/1,241) to 6.7% (54/807). The incidence (95% confidence interval) of blindness was 40.2 (25.3-63.8) per 10,000 patient-years. Baseline predictors of level of visual acuity (age, age-related macular degeneration (AMD), cataract, living alone, low self-rated health, and sedentary life-style) and speed of continued visual loss (age, AMD, diabetic retinopathy (DR), cataract, living alone, and high fasting triglycerides) were identified.</p> <p>Conclusions</p> <p>In a comprehensive assessment of predictors of visual impairment, even in a health care system allowing self-referral to free eye examinations, treatable eye pathologies such as DR and cataract emerge together with age as the most notable predictors of continued visual loss after diabetes diagnosis. Our results underline the importance of eliminating barriers to efficient eye care by increasing patients' and primary care practitioners' awareness of the necessity of regular eye examinations and timely surgical treatment.</p

Parasympathetic Activity and Blood Catecholamine Responses Following a Single Partial-Body Cryostimulation and a Whole-Body Cryostimulation

The aim of this study was to compare the effects of a single whole-body cryostimulation (WBC) and a partial-body cryostimulation (PBC) (i.e., not exposing the head to cold) on indices of parasympathetic activity and blood catecholamines. Two groups of 15 participants were assigned either to a 3-min WBC or PBC session, while 10 participants constituted a control group (CON) not receiving any cryostimulation. Changes in thermal, physiological and subjective variables were recorded before and during the 20-min after each cryostimulation. According to a qualitative statistical analysis, an almost certain decrease in skin temperature was reported for all body regions immediately after the WBC (mean decrease±90% CL, -13.7±0.7°C) and PBC (-8.3±0.3°C), which persisted up to 20-min after the session. The tympanic temperature almost certainly decreased only after the WBC session (-0.32±0.04°C). Systolic and diastolic blood pressures were very likely increased after the WBC session, whereas these changes were trivial in the other groups. In addition, heart rate almost certainly decreased after PBC (-10.9%) and WBC (-15.2%) sessions, in a likely greater proportion for WBC compared to PBC. Resting vagal-related heart rate variability indices (the root-mean square difference of successive normal R-R intervals, RMSSD, and high frequency band, HF) were very likely increased after PBC (RMSSD: +54.4%, HF: +138%) and WBC (RMSSD: +85.2%, HF: +632%) sessions without any marked difference between groups. Plasma norepinephrine concentrations were likely to very likely increased after PBC (+57.4%) and WBC (+76.2%), respectively. Finally, cold and comfort sensations were almost certainly altered after WBC and PBC, sensation of discomfort being likely more pronounced after WBC than PBC. Both acute cryostimulation techniques effectively stimulated the autonomic nervous system (ANS), with a predominance of parasympathetic tone activation. The results of this study also suggest that a whole-body cold exposure induced a larger stimulation of the ANS compared to partial-body cold exposure

The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila

Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs

Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity

Background Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods A longitudinal cohort study was conducted in 835 patients [RA = 573; SLE = 262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Ex vivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression. Findings In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12–2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09–3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion in vivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC. Interpretation FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols. Funding Medical Research Council, National Institute for Health and Care Research, Versus Arthritis

Do you get what you pay for? Sales incentives and implications for motivation and changes in turnover intention and work effort

This study investigated relations between pay-for-performance incentives designed to vary in instrumentality (annual pay-for-performance, quarterly pay-for-performance, and base pay level) and employee outcomes (self-reported work effort and turnover intention) in a longitudinal study spanning more than 2 years. After controlling for perceived instrumentality, merit pay increase, and the initial values of the dependent variables, the amount of base pay was positively related to work effort and negatively related to turnover intention, where both relationships were mediated by autonomous motivation. The amounts of quarterly and annual pay-for-performance were both positively related to controlled motivation, but were differently related to the dependent variables due to different relations with autonomous motivation

Meta-analysis of variation suggests that embracing variability improves both replicability and generalizability in preclinical research

The replicability of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets replicability has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that cannot be replicated. An alternative approach is to, instead, deliberately introduce heterogeneity, known as "heterogenization" of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischemic stroke. First, by quantifying interindividual variability across control groups, we illustrate that the amount of heterogeneity in disease state (infarct volume) differs according to methodological approach, for example, in disease induction methods and disease models. We argue that such methods may improve replicability by creating diverse and representative distribution of baseline disease state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-individual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e., low interindividual variability), as well as those where there is high interindividual variability in response; for these, latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimize variability in phenotypic outcomes, we can motivate the shift toward heterogenization and improve both the replicability and generalizability of preclinical research