Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Changes in the Placental Glucocorticoid Barrier During Rat Pregnancy: Impact on Placental Corticosterone Levels and Regulation by Progesterone 1

ABSTRACT Glucocorticoid excess in utero inhibits fetal growth and programs adverse outcomes in adult offspring. Access of maternal glucocorticoid to the glucocorticoid receptor (NR3C1) in the placenta and fetus is regulated by metabolism via the 11beta-hydroxysteroid dehydrogenase (HSD11B) enzymes, as well as multidrug resistance P-glycoprotein (ABCB1)-mediated efflux of glucocorticoids from the syncytiotrophoblast. This study determined expression of genes encoding the two HSD11B isoforms (Hsd11b1 and Hsd11b2), the two ABCB1 isoforms (Abcb1a and Abcb1b), and Nr3c1 in the junctional and labyrinth zones of rat placentas at Days 16 and 22 of normal gestation (Day 23 is term). To assess possible regulation of the Hsd11b and Abcb1 isoforms by glucocorticoids and progesterone, their placental expression was also measured at Day 22 after partial progesterone withdrawal from Day 16 (maternal ovariectomy plus full estrogen and partial progesterone replacement) or after treatment with dexamethasone acetate (1 lg/ml of drinking water from Day 13). Expression of Hsd11b1 mRNA increased in the labyrinth zone (the site of maternal-fetal exchange) from Day 16 to Day 22, whereas that of Hsd11b2 fell dramatically. Consistent with these changes, corticosterone levels increased 10-fold in the labyrinth zone over this period. Expression of both Abcb1a and Abcb1b was markedly higher in the labyrinth zone compared with the junctional zone on both days, consistent with the proposed barrier role of ABCB1 in the placenta. Nr3c1 mRNA expression was similar in the two placental zones at Day 16 but increased 3-fold in the labyrinth zone by Day 22. Partial progesterone withdrawal increased Hsd11b1 mRNA and protein expression in the labyrinth zone but decreased Nr3c1 mRNA expression. These data show that the dynamic expression patterns of the placental HSD11Bs in late gestation are associated with dramatic shifts in placental corticosterone. Moreover, the late gestational rise in labyrinthine Hsd11b1 seems to be driven by the normal prepartum fall in progesterone level. 11beta-hydroxysteroid dehydrogenase, corticosterone, P-glycoprotein, placental glucocorticoid barrier, progesteron

Associations of resting heart rate with concentrations of lipoprotein subfractions in sedentary men

In major prospective studies it has been reported that high heart rate at rest predicts the development of coronary heart disease (CHD) or cardiovascular disease (CVD) in men, but the mechanisms producing these relationships are unknown. Since lipoprotein levels contribute strongly to the risk of CHD and CVD, we examined the relationship of resting heart rate to plasma concentrations of high-density (HDL), low-density (LDL), and very low-density (VLDL) lipoproteins, apolipoprotein (apo) A-I and A-II, and serum concentrations of lipoprotein subfractions in 81 men to determine if atherogenic lipoproteins could potentially induce the reported association of heart rate with development of CHD or CVD. The significant (p less than or equal to .05) Spearman\u27s correlations for resting heart rate vs HDL2 mass (rs = - .24), HDL3 mass (rs = - .40), HDL cholesterol (rs = - .36), apo A-I (rs = - .29), triglycerides (rs = .31), VLDL cholesterol (rs = .24), VLDL mass (rs = .27), and LDL mass of Sof 0-7 subfraction (rs = .30) lend support to our hypothesis of lipoprotein-induced relationships of CHD with heart rate. The correlations of resting heart rate vs triglycerides, HDL cholesterol, HDL3 mass, VLDL mass, and LDL mass of Sof 0-7 subfraction remain significant when adjusted for adiposity, age, smoking habits, diet, and physical fitness as measured by maximum aerobic power (VO2 max) or submaximal heart rate during a graded exercise test

Remarkable resilience of forest structure and biodiversity following fire in the peri-urban bushland of Sydney, Australia

In rapidly urbanizing areas, natural vegetation becomes fragmented, making conservation planning challenging, particularly as climate change accelerates fire risk. We studied urban forest fragments in two threatened eucalypt‐dominated (scribbly gum woodland, SGW, and ironbark forest, IF) communities across ~2000 ha near Sydney, Australia, to evaluate effects of fire frequency (0– 4 in last 25 years) and time since fire (0.5 to >25 years) on canopy structure, habitat quality and biodiversity (e.g., species richness). Airborne lidar was used to assess canopy height and density, and ground‐based surveys of 148 (400 m2) plots measured leaf area index (LAI), plant species com‐ position and habitat metrics such as litter cover and hollow‐bearing trees. LAI, canopy density, litter, and microbiotic soil crust increased with time since fire in both communities, while tree and mistletoe cover increased in IF. Unexpectedly, plant species richness increased with fire frequency, owing to increased shrub richness which offset decreased tree richness in both communities. These findings indicate biodiversity and canopy structure are generally resilient to a range of times since fire and fire frequencies across this study area. Nevertheless, reduced arboreal habitat quality and subtle shifts in community composition of resprouters and obligate seeders signal early concern for a scenario of increasing fire frequency under climate change. Ongoing assessment of fire responses is needed to ensure that biodiversity, canopy structure and ecosystem function are maintained in the remaining fragments of urban forests under future climate change which will likely drive hotter and more frequent fires

Controlled in vitro delivery of voriconazole and diclofenac to the cornea using contact lenses for the treatment of Acanthamoeba keratitis

Acanthamoeba keratitis is caused by a protozoal infection of the cornea, with 80% of cases involving the improper use of contact lenses. The infection causes intense pain and is potentially blinding. However, early diagnosis improves treatment efficacy and the chances of healing. Despite the apparent accessibility of the cornea, patients do not always respond well to current eye drop treatments largely due to rapid dose loss due to blinking and nasolacrimal drainage. Here, the topical drug delivery of voriconazole alone and in combination with diclofenac via drug-loaded contact lenses, were investigated in vitro. The contact lenses were applied onto excised porcine eyeballs and maintained at 32°C under constant irrigation, with simulated tear fluid applied to mimic in vivo conditions. The drug delivered to the corneas was quantified by HPLC analysis. The system was further tested in terms of cytotoxicity and a scratch wound repopulation model, using corneal epithelial cells. Sustained drug delivery to the cornea was achieved and for voriconazole, the MIC against Acanthamoeba castellanii was attained alone and in combination with diclofenac. MTT and scratch wound data showed reasonable cell proliferation and wound repopulation at the drug doses used, supporting further development of the system to treat Acanthamoeba keratitis

The origin of cosmic rays

The search for the origin of cosmic rays is a quest of almost a hundred years. A recent theoretical proposal gives quantitative predictions, which can be tested with data. Specifically, it has been suggested, that all cosmic rays can be attributed to just three source sites: i) supernova explosions into the interstellar medium, ii) supernova explosions into a stellar wind, and iii) powerful radiogalaxies. The cosmic rays from any extragalactic source suffer from interaction with the microwave background, leading to the Greisen-Zatsepin-Kuzmin cutoff. While the particle energies, the spectrum and the chemical composition of cosmic rays over the energy range from about GeV to about 100 EeV can be interpreted in the theory, there are exciting measurements now: New measurements show that there are cosmic ray events beyond the Greisen-Zatsepin-Kuzmin cutoff. We discuss here possible sources, and specifically ask whether powerful radiogalaxies are suitable candidates. The basic concepts used here are the minimal hypothesis that the intergalactic magnetic field is given by the galaxy distribution, and the observation that radio galaxies also cluster like galaxies.Comment: Lecture at the meeting Trends in Astroparticle Physics, Stockholm September 1994, 8 pages, uuencode

Protocol for a feasibility study to inform the development of a multi centre randomised controlled trial of asthma-tailored pulmonary rehabilitation versus usual care for individuals with severe asthma

Open access articleIntroduction: Pulmonary rehabilitation with core components of exercise training and multiprofessional education is an integral part of the management of patients with chronic lung disease. International guidelines for individuals with asthma recommend exercise as exercise improves symptoms, indices of cardiopulmonary efficiency, health status and psychosocial outcome. However, there is little published evidence evaluating safety and acceptability of exercise training for individuals with severe asthma and there are concerns regarding exercise-induced asthma. We propose a feasibility study for a multicentre randomised controlled trial (RCT) of asthma-tailored pulmonary rehabilitation (asthma- tailored PR) versus usual care in individuals with severe asthma. Methods and analysis: The study will be conducted in three stages. Adults with severe asthma will be included if they have persistent symptoms despite being at step 4 or 5 of the British Thoracic Society guidelines. Stage 1: semistructured interviews will be used in a sample of 20–30 individuals with severe asthma to understand the experience and attitudes of this population towards exercise. Stage 2: eight focus groups of at least six healthcare professionals involved in the care of patients with severe asthma will be conducted to understand their attitudes towards exercise for this population. Stage 3: a small-scale RCT of the proposed multicentre RCT of asthma- tailored PR versus usual care for individuals with severe asthma will be conducted. The primary outcome measures will be recruitment, retention and adverse event rates. Semistructured interviews with participants of stage 3 will be used to identify further barriers or facilitators to participation in PR and the trial. Thematic analysis will be used for the interpretation of all interviews. Ethics and dissemination: The study results will inform the design of a larger multicentre RCT. TheNational Research Ethics Service Committee East Midland approved the study protocol