Premature Senescence and Increased TGFβ Signaling in the Absence of Tgif1

Transforming growth factor β (TGFβ) signaling regulates cell cycle progression in several cell types, primarily by inducing a G1 cell cycle arrest. Tgif1 is a transcriptional corepressor that limits TGFβ responsive gene expression. Here we demonstrate that primary mouse embryo fibroblasts (MEFs) lacking Tgif1 proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. We also provide evidence that the effects of loss of Tgif1 on proliferation and senescence are not limited to primary cells. The increased DNA damage in Tgif1 null MEFs can be partially reversed by culturing cells at physiological oxygen levels, and growth in normoxic conditions also partially rescues the proliferation defect, suggesting that in the absence of Tgif1 primary MEFs are less able to cope with elevated levels of oxidative stress. Additionally, we show that Tgif1 null MEFs are more sensitive to TGFβ-mediated growth inhibition, and that treatment with a TGFβ receptor kinase inhibitor increases proliferation of Tgif1 null MEFs. Conversely, persistent treatment of wild type cells with low levels of TGFβ slows proliferation and induces senescence, suggesting that TGFβ signaling also contributes to cellular senescence. We suggest that in the absence of Tgif1, a persistent increase in TGFβ responsive transcription and a reduced ability to deal with hyperoxic stress result in premature senescence in primary MEFs

The Effects of Wildfire on Mortality and Resources for an Arboreal Marsupial: Resilience to Fire Events but Susceptibility to Fire Regime Change

BACKGROUND: Big environmental disturbances have big ecological effects, yet these are not always what we might expect. Understanding the proximate effects of major disturbances, such as severe wildfires, on individuals, populations and habitats will be essential for understanding how predicted future increases in the frequency of such disturbances will affect ecosystems. However, researchers rarely have access to data from immediately before and after such events. Here we report on the effects of a severe and extensive forest wildfire on mortality, reproductive output and availability of key shelter resources for an arboreal marsupial. We also investigated the behavioural response of individuals to changed shelter resource availability in the post-fire environment. METHODOLOGY/PRINCIPAL FINDINGS: We fitted proximity-logging radiotransmitters to mountain brushtail possums (Trichosurus cunninghami) before, during and after the 2009 wildfires in Victoria, Australia. Surprisingly, we detected no mortality associated with the fire, and despite a significant post-fire decrease in the proportion of females carrying pouch young in the burnt area, there was no short-term post-fire population decline. The major consequence of this fire for mountain brushtail possums was the loss of over 80% of hollow-bearing trees. The types of trees preferred as shelter sites (highly decayed dead standing trees) were those most likely to collapse after fire. Individuals adapted to resource decline by being more flexible in resource selection after the fire, but not by increased resource sharing. CONCLUSIONS/SIGNIFICANCE: Despite short-term demographic resilience and behavioural adaptation following this fire, the major loss of decayed hollow trees suggests the increased frequency of stand-replacing wildfires predicted under climate change will pose major challenges for shelter resource availability for hollow-dependent fauna. Hollow-bearing trees are typically biological legacies of previous forest generations in post-fire regrowth forests but will cease to be recruited to future regrowth forests if the interval between severe fires becomes too rapid for hollow formation

HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model

Observation of Z production in proton-lead collisions at LHCb

The first observation of Z boson production in proton-lead collisions at a centre-of-mass energy per proton-nucleon pair of root(s) N N = 5TeV is presented. The data sample corresponds to an integrated luminosity of 1.6 nb(-1) collected with the LHCb detector. The Z candidates are reconstructed from pairs of oppositely charged muons with pseudorapidities between 2.0 and 4.5 and transverse momenta above 20 GeV/c. The invariant dimuon mass is restricted to the range 60-120 GeV/c. The Z production cross-section is measured to be sigma(Z ->mu+mu-) (fwd) = 13.5(-4.0)(+5.4)(stat.) +/- 1.2(syst.) nb in the direction of the proton beam and sigma(Z ->mu+mu-) (bwd) = 10.7(-5.1)(+8.4)(stat.) +/- 1.0(syst.) nb in the direction of the lead beam, where the first uncertainty is statistical and the second systematic

Measurement of Upsilon production in pp collisions at \sqrt{s} = 7 TeV

The production of Upsilon(1S), Upsilon(2S) and Upsilon(3S) mesons in proton-proton collisions at the centre-of-mass energy of sqrt(s)=7 TeV is studied with the LHCb detector. The analysis is based on a data sample of 25 pb-1 collected at the Large Hadron Collider. The Upsilon mesons are reconstructed in the decay mode Upsilon -> mu+ mu- and the signal yields are extracted from a fit to the mu+ mu- invariant mass distributions. The differential production cross-sections times dimuon branching fractions are measured as a function of the Upsilon transverse momentum pT and rapidity y, over the range pT < 15 GeV/c and 2.0 < y < 4.5. The cross-sections times branching fractions, integrated over these kinematic ranges, are measured to be sigma(pp -> Upsilon(1S) X) x B(Upsilon(1S)->mu+ mu-) = 2.29 {\pm} 0.01 {\pm} 0.10 -0.37 +0.19 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S)->mu+ mu-) = 0.562 {\pm} 0.007 {\pm} 0.023 -0.092 +0.048 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S)->mu+ mu-) = 0.283 {\pm} 0.005 {\pm} 0.012 -0.048 +0.025 nb, where the first uncertainty is statistical, the second systematic and the third is due to the unknown polarisation of the three Upsilon states.Comment: 22 pages, 7 figure

Evidence for CP violation in time-integrated D0 -> h-h+ decay rates

A search for time-integrated CP violation in D0 -> h-h+ (h=K, pi) decays is presented using 0.62 fb^-1 of data collected by LHCb in 2011. The flavor of the charm meson is determined by the charge of the slow pion in the D*+ -> D0 pi+ and D*- -> D0bar pi- decay chains. The difference in CP asymmetry between D0 -> K-K+ and D0 -> pi-pi+, Delta ACP = ACP(K-K+) - ACP(pi-pi+), is measured to be [-0.82 \pm 0.21(stat.) \pm 0.11(syst.)]%. This differs from the hypothesis of CP conservation by 3.5 standard deviations.Comment: 8 pages, 3 figures, 2 tables; v2 minor updates after journal revie

Measurement of the Bs0→J/ψK∗0B^0_s\rightarrow J/\psi K^{*0} branching fraction and angular amplitudes

A search for the decay $B^0_s\rightarrow J/\psi K^{*0}$ with $K^{*0} \rightarrow K^-\pi^+$ is performed with 0.37 fb$^{-1}$ of $pp$ collisions at $\sqrt{s}$ = 7 TeV collected by the LHCb experiment, finding a \Bs \to J\psi K^-\pi^+ peak of $114 \pm 11$ signal events. The $K^-\pi^+$ mass spectrum of the candidates in the $B^0_s$ peak is dominated by the $K^{*0}$ contribution. Subtracting the non-resonant $K^-\pi^+$ component, the branching fraction of \BsJpsiKst is $(4.4_{-0.4}^{+0.5} \pm 0.8) \times 10^{-5}$, where the first uncertainty is statistical and the second systematic. A fit to the angular distribution of the decay products yields the \Kst polarization fractions $f_L = 0.50 \pm 0.08 \pm 0.02$ and $f_{||} = 0.19^{+0.10}_{-0.08} \pm 0.02$

The associations between seven different types of physical activity and the incidence of fracture at seven sites in healthy postmenopausal UK women

There is a paucity of information on associations between specific types of physical activity and fracture risk at different sites in otherwise healthy postmenopausal women. Therefore, we examined risk of fracture at 7 different sites associated with 7 different types of physical activity in the population-based prospective UK Million Women Study. A total of 371,279 postmenopausal women (mean age 59.8 years), rating their health as good or excellent and reporting participation in walking, cycling, gardening, doing housework, yoga, dance and sports club activities, were followed for site-specific incident fracture through record linkage to national databases on day-case and overnight hospital admissions. Cox regression yielded adjusted relative risks (RRs) and, because of the large number of statistical tests done, 99% confidence intervals (CIs) for fracture at 7 different sites in relation to 7 different physical activities. During an average follow-up of 12 years, numbers with a first site-specific fracture were: humerus (2341), forearm (1238), wrist (7358), hip (4354), femur (not neck) (617), lower leg (1184), and ankle (3629). For upper limb fractures there was significant heterogeneity across the 7 activity types (test for heterogeneity p=0.004), with gardening more than one hour/week associated with a lower risk (RR=0.91, 99%CI 0.86-0.96; p<0.0001), whereas cycling more than an hour/week was associated with an increased risk (RR=1.11, 99%CI 1.00-1.23; p=0.008). For fractures of the lower limb (including hip) there was no significant heterogeneity by type of activity, with significant approximately 5-15% reductions in risk associated with most activities, except cycling. For hip fractures, there was no significant heterogeneity by type of activity, but with significant 15-20% reductions in risk associated with walking for 1 hour/day and participating in yoga and sporting activities. Physical activity is a modifiable risk factor for fracture, but the effects differ between different types of activities and different fracture sites. This article is protected by copyright. All rights reserved

The associations between seven different types of physical activity and the incidence of fracture at seven sites in healthy postmenopausal UK women

There is a paucity of information on associations between specific types of physical activity and fracture risk at different sites in otherwise healthy postmenopausal women. Therefore, we examined risk of fracture at 7 different sites associated with 7 different types of physical activity in the population-based prospective UK Million Women Study. A total of 371,279 postmenopausal women (mean age 59.8 years), rating their health as good or excellent and reporting participation in walking, cycling, gardening, doing housework, yoga, dance and sports club activities, were followed for site-specific incident fracture through record linkage to national databases on day-case and overnight hospital admissions. Cox regression yielded adjusted relative risks (RRs) and, because of the large number of statistical tests done, 99% confidence intervals (CIs) for fracture at 7 different sites in relation to 7 different physical activities. During an average follow-up of 12 years, numbers with a first site-specific fracture were: humerus (2341), forearm (1238), wrist (7358), hip (4354), femur (not neck) (617), lower leg (1184), and ankle (3629). For upper limb fractures there was significant heterogeneity across the 7 activity types (test for heterogeneity p=0.004), with gardening more than one hour/week associated with a lower risk (RR=0.91, 99%CI 0.86-0.96; p&lt;0.0001), whereas cycling more than an hour/week was associated with an increased risk (RR=1.11, 99%CI 1.00-1.23; p=0.008). For fractures of the lower limb (including hip) there was no significant heterogeneity by type of activity, with significant approximately 5-15% reductions in risk associated with most activities, except cycling. For hip fractures, there was no significant heterogeneity by type of activity, but with significant 15-20% reductions in risk associated with walking for 1 hour/day and participating in yoga and sporting activities. Physical activity is a modifiable risk factor for fracture, but the effects differ between different types of activities and different fracture sites. This article is protected by copyright. All rights reserved