On the continuous spectral component of the Floquet operator for a periodically kicked quantum system

By a straightforward generalisation, we extend the work of Combescure from rank-1 to rank-N perturbations. The requirement for the Floquet operator to be pure point is established and compared to that in Combescure. The result matches that in McCaw. The method here is an alternative to that work. We show that if the condition for the Floquet operator to be pure point is relaxed, then in the case of the delta-kicked Harmonic oscillator, a singularly continuous component of the Floquet operator spectrum exists. We also provide an in depth discussion of the conjecture presented in Combescure of the case where the unperturbed Hamiltonian is more general. We link the physics conjecture directly to a number-theoretic conjecture of Vinogradov and show that a solution of Vinogradov's conjecture solves the physics conjecture. The result is extended to the rank-N case. The relationship between our work and the work of Bourget on the physics conjecture is discussed.Comment: 25 pages, published in Journal of Mathematical Physic

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1

The Merging of a Coronal Dimming and the Southern Polar Coronal Hole

We report on the merging between the southern polar coronal hole and an adjacent coronal dimming induced by a coronal mass ejection on 2022 March 18, resulting in the merged region persisting for at least 72 hr. We use remote sensing data from multiple co-observing spacecraft to understand the physical processes during this merging event. The evolution of the merger is examined using Extreme-UltraViolet (EUV) images obtained from the Atmospheric Imaging Assembly on board the Solar Dynamic Observatory and Extreme Ultraviolet Imager, which is on board the Solar Orbiter spacecraft. The plasma dynamics are quantified using spectroscopic data obtained from the EUV Imaging Spectrometer on board Hinode. The photospheric magnetograms from the Helioseismic and Magnetic Imager are used to derive the magnetic field properties. To our knowledge, this work is the first spectroscopical analysis of the merging of two open-field structures. We find that the coronal hole and the coronal dimming become indistinguishable after the merging. The upflow speeds inside the coronal dimming become more similar to that of a coronal hole, with a mixture of plasma upflows and downflows observable after the merging. The brightening of the bright points and the appearance of coronal jets inside the merged region further imply ongoing reconnection processes. We propose that component reconnection between the coronal hole and coronal dimming fields plays an important role during this merging event because the footpoint switching resulting from the reconnection allows the coronal dimming to intrude onto the boundary of the southern polar coronal hole

A review of clinical decision-making: Models and current research

Aims and objectives: The aim of this paper was to review the current literature with respect to clinical decision-making models and the educational application of models to clinical practice. This was achieved by exploring the function and related research of the three available models of clinical decision making: information processing model, the intuitive-humanist model and the clinical decision making model. Background: Clinical decision-making is a unique process that involves the interplay between knowledge of pre-existing pathological conditions, explicit patient information, nursing care and experiential learning. Historically, two models of clinical decision making are recognised from the literature; the information processing model and the intuitive-humanist model. The usefulness and application of both models has been examined in relation the provision of nursing care and care related outcomes. More recently a third model of clinical decision making has been proposed. This new multidimensional model contains elements of the information processing model but also examines patient specific elements that are necessary for cue and pattern recognition. Design: Literature review Methods: Evaluation of the literature generated from MEDLINE, CINAHL, OVID, PUBMED and EBESCO systems and the Internet from 1980 – November 2005

Stereotactically guided breast biopsy: a review

The aims of this review are to compare and contrast the available stereotactic equipment, and to describe the variety of needle types used and their affect on pathological results and subsequent patient management. Initial stereotactic devices were “added-on” to analogue mammography units and have been replaced by prone or ducubitus equipment using digital image acquisition. Biopsies use either 14-G core biopsy (CB) needles or vacuum-assisted biopsies (VAB). Vacuum-assisted biopsy systems consistently out-perform 14-G CB with reduced need for diagnostic or multi-treatment surgery. The false-negative rate is 8% for 14-G CB compared with 0.7% for VAB. There is a risk of underestimating the disease present for lesions of uncertain malignant potential (Cat B3) and suspicious of malignancy (Cat B4) results with 25% of patients with a B3 biopsy found to have cancer at subsequent surgery and 66% of those with a B4 biopsy. A CB diagnosis of in situ malignancy is upgraded to invasive disease at surgery in 15-36% of patients undergoing CB and of the order of 10% with VAB. A high degree of diagnostic accuracy and hence safe patient care can only be achieved by meticulous attention to technique and multi-disciplinary cooperation

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Global parameter search reveals design principles of the mammalian circadian clock

Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/ dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level

Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an 'Immune Cold' Phenotype Associated with Poor Survival.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an 'immune cold' tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC