Roles for the coactivators CBP and p300 and the APC/C E3 ubiquitin ligase in E1A-dependent cell transformation

Adenovirus early region 1A (E1A) possesses potent transforming activity when expressed in concert with activated ras or E1B genes in in vitro tissue culture systems such as embryonic human retinal neuroepithelial cells or embryonic rodent epithelial and fibroblast cells. Early region 1A has thus been used extensively and very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. In this regard, roles for the E1A-binding proteins pRb, p107, p130, cyclic AMP response element-binding protein (CBP)/p300, p400, TRRAP and CtBP in cellular transformation have been established. However, the mechanisms by which E1A promotes transformation through interaction with these partner proteins are not fully delineated. In this review, we focus on recent advances in our understanding of CBP/p300 function, particularly with regard to its relationship to the anaphase-promoting complex/cyclosome E3 ubiquitin ligase, which has recently been shown to interact and affect the activity of CBP/p300 through interaction domains that are evolutionarily conserved in E1A

Spontaneous vortices in the formation of Bose-Einstein condensates

Phase transitions are ubiquitous in nature, ranging from protein folding and denaturisation, to the superconductor-insulator quantum phase transition, to the decoupling of forces in the early universe. Remarkably, phase transitions can be arranged into universality classes, where systems having unrelated microscopic physics exhibit identical scaling behaviour near the critical point. Here we present an experimental and theoretical study of the Bose-Einstein condensation phase transition of an atomic gas, focusing on one prominent universal element of phase transition dynamics: the spontaneous formation of topological defects during a quench through the transition. While the microscopic dynamics of defect formation in phase transitions are generally difficult to investigate, particularly for superfluid phase transitions, Bose-Einstein condensates (BECs) offer unique experimental and theoretical opportunities for probing such details. Although spontaneously formed vortices in the condensation transition have been previously predicted to occur, our results encompass the first experimental observations and statistical characterisation of spontaneous vortex formation in the condensation transition. Using microscopic theories that incorporate atomic interactions and quantum and thermal fluctuations of a finite-temperature Bose gas, we simulate condensation and observe vortex formation in close quantitative agreement with our experimental results. Our studies provide further understanding of the development of coherence in superfluids, and may allow for direct investigation of universal phase-transition dynamics.Comment: 14 pages, 6 figures. Accepted for publication in Nature. Supplementary movie files are available at http://www.physics.uq.edu.au/people/mdavis/spontaneous_vortice

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Keratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures. Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 min precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1-associated proteins prevented nuclear volume reduction. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction

Non-allergic rhinitis: a case report and review

Rhinitis is characterized by rhinorrhea, sneezing, nasal congestion, nasal itch and/or postnasal drip. Often the first step in arriving at a diagnosis is to exclude or diagnose sensitivity to inhalant allergens. Non-allergic rhinitis (NAR) comprises multiple distinct conditions that may even co-exist with allergic rhinitis (AR). They may differ in their presentation and treatment. As well, the pathogenesis of NAR is not clearly elucidated and likely varied. There are many conditions that can have similar presentations to NAR or AR, including nasal polyps, anatomical/mechanical factors, autoimmune diseases, metabolic conditions, genetic conditions and immunodeficiency. Here we present a case of a rare condition initially diagnosed and treated as typical allergic rhinitis vs. vasomotor rhinitis, but found to be something much more serious. This case illustrates the importance of maintaining an appropriate differential diagnosis for a complaint routinely seen as mundane. The case presentation is followed by a review of the potential causes and pathogenesis of NAR

Neural Circuits Underlying Rodent Sociality: A Comparative Approach

All mammals begin life in social groups, but for some species, social relationships persist and develop throughout the course of an individual’s life. Research in multiple rodent species provides evidence of relatively conserved circuitry underlying social behaviors and processes such as social recognition and memory, social reward, and social approach/avoidance. Species exhibiting different complex social behaviors and social systems (such as social monogamy or familiarity preferences) can be characterized in part by when and how they display specific social behaviors. Prairie and meadow voles are closely related species that exhibit similarly selective peer preferences but different mating systems, aiding direct comparison of the mechanisms underlying affiliative behavior. This chapter draws on research in voles as well as other rodents to explore the mechanisms involved in individual social behavior processes, as well as specific complex social patterns. Contrasts between vole species exemplify how the laboratory study of diverse species improves our understanding of the mechanisms underlying social behavior. We identify several additional rodent species whose interesting social structures and available ecological and behavioral field data make them good candidates for study. New techniques and integration across laboratory and field settings will provide exciting opportunities for future mechanistic work in non-model species

Seasonal Patterns of Body Temperature Daily Rhythms in Group-Living Cape Ground Squirrels Xerus inauris

Organisms respond to cyclical environmental conditions by entraining their endogenous biological rhythms. Such physiological responses are expected to be substantial for species inhabiting arid environments which incur large variations in daily and seasonal ambient temperature (Ta). We measured core body temperature (Tb) daily rhythms of Cape ground squirrels Xerus inauris inhabiting an area of Kalahari grassland for six months from the Austral winter through to the summer. Squirrels inhabited two different areas: an exposed flood plain and a nearby wooded, shady area, and occurred in different social group sizes, defined by the number of individuals that shared a sleeping burrow. Of a suite of environmental variables measured, maximal daily Ta provided the greatest explanatory power for mean Tb whereas sunrise had greatest power for Tb acrophase. There were significant changes in mean Tb and Tb acrophase over time with mean Tb increasing and Tb acrophase becoming earlier as the season progressed. Squirrels also emerged from their burrows earlier and returned to them later over the measurement period. Greater increases in Tb, sometimes in excess of 5°C, were noted during the first hour post emergence, after which Tb remained relatively constant. This is consistent with observations that squirrels entered their burrows during the day to ‘offload’ heat. In addition, greater Tb amplitude values were noted in individuals inhabiting the flood plain compared with the woodland suggesting that squirrels dealt with increased environmental variability by attempting to reduce their Ta-Tb gradient. Finally, there were significant effects of age and group size on Tb with a lower and less variable Tb in younger individuals and those from larger group sizes. These data indicate that Cape ground squirrels have a labile Tb which is sensitive to a number of abiotic and biotic factors and which enables them to be active in a harsh and variable environment

A Melodic Contour Repeatedly Experienced by Human Near-Term Fetuses Elicits a Profound Cardiac Reaction One Month after Birth

Human hearing develops progressively during the last trimester of gestation. Near-term fetuses can discriminate acoustic features, such as frequencies and spectra, and process complex auditory streams. Fetal and neonatal studies show that they can remember frequently recurring sounds. However, existing data can only show retention intervals up to several days after birth.Here we show that auditory memories can last at least six weeks. Experimental fetuses were given precisely controlled exposure to a descending piano melody twice daily during the 35(th), 36(th), and 37(th) weeks of gestation. Six weeks later we assessed the cardiac responses of 25 exposed infants and 25 naive control infants, while in quiet sleep, to the descending melody and to an ascending control piano melody. The melodies had precisely inverse contours, but similar spectra, identical duration, tempo and rhythm, thus, almost identical amplitude envelopes. All infants displayed a significant heart rate change. In exposed infants, the descending melody evoked a cardiac deceleration that was twice larger than the decelerations elicited by the ascending melody and by both melodies in control infants.Thus, 3-weeks of prenatal exposure to a specific melodic contour affects infants 'auditory processing' or perception, i.e., impacts the autonomic nervous system at least six weeks later, when infants are 1-month old. Our results extend the retention interval over which a prenatally acquired memory of a specific sound stream can be observed from 3-4 days to six weeks. The long-term memory for the descending melody is interpreted in terms of enduring neurophysiological tuning and its significance for the developmental psychobiology of attention and perception, including early speech perception, is discussed

Systematic review of the evidence relating FEV1 decline to giving up smoking

<p>Abstract</p> <p>Background</p> <p>The rate of forced expiratory volume in 1 second (FEV₁) decline ("beta") is a marker of chronic obstructive pulmonary disease risk. The reduction in beta after quitting smoking is an upper limit for the reduction achievable from switching to novel nicotine delivery products. We review available evidence to estimate this reduction and quantify the relationship of smoking to beta.</p> <p>Methods</p> <p>Studies were identified, in healthy individuals or patients with respiratory disease, that provided data on beta over at least 2 years of follow-up, separately for those who gave up smoking and other smoking groups. Publications to June 2010 were considered. Independent beta estimates were derived for four main smoking groups: never smokers, ex-smokers (before baseline), quitters (during follow-up) and continuing smokers. Unweighted and inverse variance-weighted regression analyses compared betas in the smoking groups, and in continuing smokers by amount smoked, and estimated whether beta or beta differences between smoking groups varied by age, sex and other factors.</p> <p>Results</p> <p>Forty-seven studies had relevant data, 28 for both sexes and 19 for males. Sixteen studies started before 1970. Mean follow-up was 11 years. On the basis of weighted analysis of 303 betas for the four smoking groups, never smokers had a beta 10.8 mL/yr (95% confidence interval (CI), 8.9 to 12.8) less than continuing smokers. Betas for ex-smokers were 12.4 mL/yr (95% CI, 10.1 to 14.7) less than for continuing smokers, and for quitters, 8.5 mL/yr (95% CI, 5.6 to 11.4) less. These betas were similar to that for never smokers. In continuing smokers, beta increased 0.33 mL/yr per cigarette/day. Beta differences between continuing smokers and those who gave up were greater in patients with respiratory disease or with reduced baseline lung function, but were not clearly related to age or sex.</p> <p>Conclusion</p> <p>The available data have numerous limitations, but clearly show that continuing smokers have a beta that is dose-related and over 10 mL/yr greater than in never smokers, ex-smokers or quitters. The greater decline in those with respiratory disease or reduced lung function is consistent with some smokers having a more rapid rate of FEV₁decline. These results help in designing studies comparing continuing smokers of conventional cigarettes and switchers to novel products.</p