The Wenchuan earthquake was a catastrophic earthquake in China. The aim of this study is to explore longitudinally the rates of post-traumatic stress disorder (PTSD) and depression in adolescents ...after the Wenchuan earthquake, and to identify independent predictors of PTSD.
PTSD and depression symptoms among adolescents at 6, 12 and 18 months after the Wenchuan earthquake were investigated using the PTSD Checklist Civilian Version and the Beck Depression Inventory (BDI). Subjects in this study included 548 high school student survivors in a local boarding high school.
The rates of PTSD symptoms were 9.7%, 1.3% and 1.6% at the 6-, 12- and 18-month follow-ups, respectively. BDI scores were found to be the best predictor of severity of PTSD at 6, 12 and 18 months. Gender was another variable contributing significantly to PTSD at 6 and 12 months after the earthquake. In the 12-month follow-up, home damage was found to be a predictor of severity of PTSD symptoms. Being a child with siblings was found to be a predictor of severity of PTSD symptoms at 12 and 18 months after the earthquake.
PTSD symptoms changed gradually at various stages after the earthquake. Depression symptoms were predictive of PTSD symptoms in the 18-month follow-up study. Other predictors of PTSD symptoms included female gender and being a child with siblings. The results of this study may be helpful for further mental health interventions for adolescents after earthquakes.
FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic ...fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.
High-energy photons from the Crab Nebula
The Crab Nebula contains a pulsar that excites the surrounding gas to emit high-energy radiation. The combination of the pulsar's youth and nearby location ...makes the nebula the brightest gamma-ray source in the sky. The LHAASO Collaboration report observations of this source at energies of tera– to peta–electron volts, extending the spectrum of this prototypical object. They combine these data with observations at lower energies to model the physics of the emission process. The multiwave-length data can be explained by a combination of synchrotron radiation and inverse Compton scattering.
Science
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425
Detection of the Crab Nebula at peta–electron volt energies constrains the gamma-ray emission mechanism.
The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10
−4
to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10
36
ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
An earth system model has been developed at Beijing Normal University (Beijing Normal University Earth System Model, BNU-ESM); the model is based on several widely evaluated climate model components ...and is used to study mechanisms of ocean-atmosphere interactions, natural climate variability and carbon-climate feedbacks at interannual to interdecadal time scales. In this paper, the model structure and individual components are described briefly. Further, results for the CMIP5 (Coupled Model Intercomparison Project phase 5) pre-industrial control and historical simulations are presented to demonstrate the model's performance in terms of the mean model state and the internal variability. It is illustrated that BNU-ESM can simulate many observed features of the earth climate system, such as the climatological annual cycle of surface-air temperature and precipitation, annual cycle of tropical Pacific sea surface temperature (SST), the overall patterns and positions of cells in global ocean meridional overturning circulation. For example, the El Niño-Southern Oscillation (ENSO) simulated in BNU-ESM exhibits an irregular oscillation between 2 and 5 years with the seasonal phase locking feature of ENSO. Important biases with regard to observations are presented and discussed, including warm SST discrepancies in the major upwelling regions, an equatorward drift of midlatitude westerly wind bands, and tropical precipitation bias over the ocean that is related to the double Intertropical Convergence Zone (ITCZ).
A novel approach is proposed to demonstrate the two-photon Breit-Wheeler process by using collimated and wide-bandwidth γ-ray pulses driven by 10-PW lasers. Theoretical calculations suggest that more ...than 3.2×10^{8} electron-positron pairs with a divergence angle of 7° can be created per shot, and the signal-to-noise ratio is higher than 10^{3}. The positron signal, which is roughly 100 times higher than the detection limit, can be measured by using the existing spectrometers. This approach, which could demonstrate the e^{-}e^{+} pair creation process from two photons, would provide important tests for two-photon physics and other fundamental physical theories.
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FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts ...(MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7Epi(R) cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7Epi(R) cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence.
Lamin B1 is a component of the nuclear lamina and plays a critical role in maintaining nuclear architecture, regulating gene expression and modulating chromatin positioning. We have previously shown ...that LMNB1 gene duplications cause autosomal dominant leukodystrophy (ADLD), a fatal adult onset demyelinating disease. The mechanisms by which increased LMNB1 levels cause ADLD are unclear. To address this, we used a transgenic mouse model where Lamin B1 overexpression is targeted to oligodendrocytes. These mice showed severe vacuolar degeneration of the spinal cord white matter together with marked astrogliosis, microglial infiltration, and secondary axonal damage. Oligodendrocytes in the transgenic mice revealed alterations in histone modifications favoring a transcriptionally repressed state. Chromatin changes were accompanied by reduced expression of genes involved in lipid synthesis pathways, many of which are known to play important roles in myelin regulation and are preferentially expressed in oligodendrocytes. Decreased lipogenic gene expression resulted in a significant reduction in multiple classes of lipids involved in myelin formation. Many of these gene expression changes and lipid alterations were observed even before the onset of the phenotype, suggesting a causal role. Our findings establish, for the first time, a link between LMNB1 and lipid synthesis in oligodendrocytes, and provide a mechanistic framework to explain the age dependence and white matter involvement of the disease phenotype. These results have implications for disease pathogenesis and may also shed light on the regulation of lipid synthesis pathways in myelin maintenance and turnover.
Autosomal dominant leukodystrophy (ADLD) is fatal neurological disorder caused by increased levels of the nuclear protein, Lamin B1. The disease is characterized by an age-dependent loss of myelin, the fatty sheath that covers nerve fibers. We have studied a mouse model where Lamin B1 level are increased in oligodendrocytes, the cell type that produces myelin in the CNS. We demonstrate that destruction of myelin in the spinal cord is responsible for the degenerative phenotype in our mouse model. We show that this degeneration is mediated by reduced expression of lipid synthesis genes and the subsequent reduction in myelin enriched lipids. These findings provide a mechanistic framework to explain the age dependence and tissue specificity of the ADLD disease phenotype.
The forkhead transcription factor FOXM1 has a key role in DNA damage response, and its deregulated overexpression is associated with genotoxic drug resistance in breast cancer. However, little is ...known about the posttranslational mechanisms by which FOXM1 expression is regulated by genotoxic agents and how they are deregulated in resistant cells. Initial co-immunoprecipitation studies verified previous proteomic analysis finding that the OTUB1 is a novel FOXM1-interacting protein. Western blot analysis showed that both OTUB1 and FOXM1 expression reduced upon genotoxic agent treatment in MCF-7 cells, but remained relatively constant in resistant cells. FOXM1 expression reduced upon OTUB1 depletion by siRNA and increased with OTUB1 overexpression in MCF-7 cells, arguing that OTUB1 positively regulates FOXM1 expression. In agreement, co-immunoprecipitation experiments demonstrated that FOXM1 expression is associated with OTUB1 binding but inversely correlates with conjugation to the protein degradation-associated Lys-48-linked ubiquitin-chains. Overexpression of wild-type (WT) OTUB1, but not the OTUB1(C91S) mutant, disrupted the formation of Lys48-linked ubiquitin-conjugates on FOXM1. Importantly, knockdown of OTUB1 by siRNA resulted in an increase in turnover of FOXM1 in MCF-7 cells treated with the protein synthesis inhibitor cycloheximide, whereas overexpression of WT OTUB1, but not the OTUB1(C91S) mutant, significantly enhances the half-life of FOXM1. In addition, proliferative and clonogenic assays also show that OTUB1 can enhance the proliferative rate and epirubicin resistance through targeting FOXM1, as OTUB1 has little effect on FOXM1-deficient cells. The physiological relevance of the regulation of FOXM1 by OTUB1 is further underscored by the significant correlations between FOXM1 and OTUB1 expression in breast cancer patient samples. Cox-regression survival analysis indicates that OTUB1 overexpression is linked to poorer outcome in particular in patients treated with chemotherapy. Collectively, these data suggest that OTUB1 limits the ubiquitination and degradation of FOXM1 in breast cancer and has a key role in genotoxic agent resistance.
First principles calculations reveal that interface orientation plays a decisive role in determining the cohesion properties of Mo-TiC interfaces, i.e., the addition of TiC (111) surface to Mo (110) ...surface could increase the cohesion strength and toughness/ductility of Mo (110) surface, whereas TiC (100) surface would decrease the cohesion strength and toughness/ductility of Mo (100) or Mo (110) surface. The present calculated results are deeply understood in terms of electronic structure, agree well with experimental observations, and could clarify the two experimental controversies regarding the effects of TiC on cohesion strength and fracture toughness of Mo in the literature.
•Interface orientation play a decisive role in determining the cohesion properties of Mo-TiC interfaces.•The Mo(110)-TiC(111)-KS interface is thermodynamically favorable and should be preferred in actual situations .•The present calculated results could clarify the two experimental controversies .
Applying the thermodynamic extremal principle, a model for grain growth and densification in the final stage of sintering of doped ceramics was derived, with segregation-dependent interfacial ...energies and mobilities (or diffusivities). The model demonstrated an interdependence between the driving forces of grain growth and densification during sintering evolution, observed because the surface energy contributes positively to the driving force of grain growth while the GB energy negatively to the driving force of densification. The model was tested in alumina as a host system, and calculations demonstrate that dopants with more negative GB (or surface) segregation enthalpy or which cause lower GB diffusion coefficient can induce higher relative densities at a given grain size. Comparatively studying yttria- and lanthana-doped alumina, the lanthana doping showed significantly enhanced sintering attributed to the larger La
3+
radius causing a more negative GB segregation energy. This present model is expected to help dopant designing to improve control over sintering.
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