Disentangling Cooper-pair formation above Tc from the pseudogap state in the cuprates

The discovery of the pseudogap in the cuprates created significant excitement amongst physicists as it was believed to be a signature of pairing, in some cases well above the room temperature. In this "pre-formed pairs" scenario, the formation of pairs without quantum phase rigidity occurs below T*. These pairs condense and develop phase coherence only below Tc. In contrast, several recent experiments reported that the pseudogap and superconducting states are characterized by two different energy scales, pointing to a scenario, where the two compete. However a number of transport, magnetic, thermodynamic and tunneling spectroscopy experiments consistently detect a signature of phase-fluctuating superconductivity above leaving open the question of whether the pseudogap is caused by pair formation or not. Here we report the discovery of a spectroscopic signature of pair formation and demonstrate that in a region of the phase diagram commonly referred to as the "pseudogap", two distinct states coexist: one that persists to an intermediate temperature Tpair and a second that extends up to T*. The first state is characterized by a doping independent scaling behavior and is due to pairing above Tc, but significantly below T*. The second state is the "proper" pseudogap - characterized by a "checker board" pattern in STM images, the absence of pair formation, and is likely linked to Mott physics of pristine CuO2 planes. Tpair has a universal value around 130-150K even for materials with very different Tc, likely setting limit on highest, attainable Tc in cuprates. The observed universal scaling behavior with respect to Tpair indicates a breakdown of the classical picture of phase fluctuations in the cuprates.Comment: 9 pages, 4 figure

Staff unavailability and safe staffing: Are headroom allowances 'realistic'?

Background “Hours per patient day” (HPPD) is an internationally recognised resourcing metric used to measure direct nursing care hours. However, hospitals often under-estimate indirect time (unavailability) and specify unrealistic targets for planned unavailability (“headroom”). Aims To investigate the disparities between planned unavailability (“headroom”) and actual staff unavailability. Methods Data were collected from the e-rostering systems of 87 NHS Trusts. This was compared with published data from 35 roster policies. Results Many hospitals use headroom as a Key Performance Indicator (KPI) and set targets for its components in their roster policies. This research highlights large variations in unavailability (15.8% to 33.6%) and lower variations in headroom (16-26%). Conclusions Hospitals operationalise headroom around an idealised ‘target’ value. This may be detrimental. Compelling a unit with unavailability between 28-30%, to adopt an institution-wide headroom of, say, 22% may, at best, increase spending on bank/agency staff, or, at worse, jeopardise patient safety

Appearance of fluctuating stripes at the onset of the pseudogap in the high-Tc Superconductor Bi2Sr2CaCu2O8+x

Doped Mott insulators have been shown to have a strong propensity to form patterns of holes and spins often referred to as stripes. In copper-oxides, doping also gives rise to the pseudogap state, which transforms into a high temperature superconductor with sufficient doping or by reducing the temperature. A long standing question has been the interplay between pseudogap, which is generic to all hole-doped cuprates, and stripes, whose static form occurs in only one family of cuprates over a narrow range of the phase diagram. Here we examine the spatial reorganization of electronic states with the onset of the pseudogap state at T* in the high-temperature superconductor Bi2Sr2CaCu2O8+x using spectroscopic mapping with the scanning tunneling microscope (STM). We find that the onset of the pseudogap phase coincides with the appearance of electronic patterns that have the predicted characteristics of fluctuating stripes. As expected, the stripe patterns are strongest when the hole concentration in the CuO2 planes is close to 1/8 (per Cu). While demonstrating that the fluctuating stripes emerge with the onset of the pseudogap state and occur over a large part of the cuprate phase diagram, our experiments indicate that they are a consequence of pseudogap behavior rather than its cause.Comment: preprint version, 25 pages including supplementary informatio

The Werner Syndrome Protein Suppresses Telomeric Instability Caused by Chromium (VI) Induced DNA Replication Stress

Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)-induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)-induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration

The Role of Early Life Experience and Species Differences in Alcohol Intake in Microtine Rodents

Social relationships have important effects on alcohol drinking. There are conflicting reports, however, about whether early-life family structure plays an important role in moderating alcohol use in humans. We have previously modeled social facilitation of alcohol drinking in peers in socially monogamous prairie voles. We have also modeled the effects of family structure on the development of adult social and emotional behaviors. Here we assessed whether alcohol intake would differ in prairie voles reared by both parents compared to those reared by a single mother. We also assessed whether meadow voles, a closely related species that do not form lasting reproductive partnerships, would differ in alcohol drinking or in the effect of social influence on drinking. Prairie voles were reared either bi-parentally (BP) or by a single mother (SM). BP- and SM-reared adult prairie voles and BP-reared adult meadow voles were given limited access to a choice between alcohol (10%) and water over four days and assessed for drinking behavior in social and non-social drinking environments. While alcohol preference was not different between species, meadow voles drank significantly lower doses than prairie voles. Meadow voles also had significantly higher blood ethanol concentrations than prairie voles after receiving the same dose, suggesting differences in ethanol metabolism. Both species, regardless of rearing condition, consumed more alcohol in the social drinking condition than the non-social condition. Early life family structure did not significantly affect any measure. Greater drinking in the social condition indicates that alcohol intake is influenced similarly in both species by the presence of a peer. While the ability of prairie voles to model humans may be limited, the lack of differences in alcohol drinking in BP- and SM-reared prairie voles lends biological support to human studies demonstrating no effect of single-parenting on alcohol abuse

The Mitochondrial Genome Is a “Genetic Sanctuary” during the Oncogenic Process

Since Otto Warburg linked mitochondrial physiology and oncogenesis in the 1930s, a number of studies have focused on the analysis of the genetic basis for the presence of aerobic glycolysis in cancer cells. However, little or no evidence exists today to indicate that mtDNA mutations are directly responsible for the initiation of tumor onset. Based on a model of gliomagenesis in the mouse, we aimed to explore whether or not mtDNA mutations are associated with the initiation of tumor formation, maintenance and aggressiveness. We reproduced the different molecular events that lead from tumor initiation to progression in the mouse glioma. In human gliomas, most of the genetic alterations that have been previously identified result in the aberrant activation of different signaling pathways and deregulation of the cell cycle. Our data indicates that mitochondrial dysfunction is associated with reactive oxygen species (ROS) generation, leading to increased nuclear DNA (nDNA) mutagenesis, but maintaining the integrity of the mitochondrial genome. In addition, mutational stability has been observed in entire mtDNA of human gliomas; this is in full agreement with the results obtained in the cancer mouse model. We use this model as a paradigm of oncogenic transformation due to the fact that mutations commonly found in gliomas appear to be the most common molecular alterations leading to tumor development in most types of human cancer. Our results indicate that the mtDNA genome is kept by the cell as a “genetic sanctuary” during tumor development in the mouse and humans. This is compatible with the hypothesis that the mtDNA molecule plays an essential role in the control of the cellular adaptive survival response to tumor-induced oxidative stress. The integrity of mtDNA seems to be a necessary element for responding to the increased ROS production associated with the oncogenic process

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously

Predicting Weight Outcomes in Preadolescence: The Role of Toddlers? Self-regulation Skills and the Temperament Dimension of Pleasure

Objective To investigate the role of toddlers? self-regulation skills and temperament in predicting weight outcomes in preadolescence. Method Participants for this study included 195 children (114 girls) obtained from three different cohorts participating in a larger ongoing longitudinal study. At 2 years of age, participants participated in several laboratory tasks designed to assess their self-regulation abilities, including emotion regulation, sustained attention, and delay of gratification, while parents filled out a temperament questionnaire to assess toddlers? pleasure expression. Height and weight measures were collected when children were 4, 5, 7, and 10 years of age. Children also filled out a body image and eating questionnaire at the 10 year visit. Results Self-regulation skills in toddlers were associated with both BMI development, pediatric obesity, and body image/eating concerns. The temperament dimension of pleasure was also associated with BMI development and pediatric obesity but not body image/eating concerns. Conclusion Self-regulation difficulties across domains as well as temperament based pleasure in toddlers represented significant individual risk factors for the development of pediatric obesity eight years later. Early self-regulation difficulties also contributed to body image and eating concerns that typically accompanied overweight children. The mechanisms by which early self-regulation skills and temperament based pleasure may contribute to the development of pediatric obesity and associated weight concerns are discussed

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression