69 research outputs found
Non-adiabatic and time-resolved photoelectron spectroscopy for molecular systems
We quantify the non-adiabatic contributions to the vibronic sidebands of
equilibrium and explicitly time-resolved non-equilibrium photoelectron spectra
for a vibronic model system of Trans-Polyacetylene. Using exact
diagonalization, we directly evaluate the sum-over-states expressions for the
linear-response photocurrent. We show that spurious peaks appear in the
Born-Oppenheimer approximation for the vibronic spectral function, which are
not present in the exact spectral function of the system. The effect can be
traced back to the factorized nature of the Born-Oppenheimer initial and final
photoemission states and also persists when either only initial, or final
states are replaced by correlated vibronic states. Only when correlated initial
and final vibronic states are taken into account, the spurious spectral weights
of the Born-Oppenheimer approximation are suppressed. In the non-equilibrium
case, we illustrate for an initial Franck-Condon excitation and an explicit
pump-pulse excitation how the vibronic wavepacket motion of the system can be
traced in the time-resolved photoelectron spectra as function of the pump-probe
delay
Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma
A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/− and p53−/− mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30% of radiation-induced tumors from both p53+/− and p53−/− mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene
Homeodomain Interacting Protein Kinase 2 Activation Compromises Endothelial Cell Response to Laminar Flow: Protective Role of p21waf1,cip1,sdi1
BACKGROUND: In the cardiovascular system, laminar shear stress (SS) is one of the most important source of endothelial protecting signals. Physical and chemical agents, however, including ionising radiations and anticancer drugs, may injure endothelial cells determining an increase in oxidative stress and genotoxic damage. Whether the SS protective function remains intact in the presence of strong oxidants or DNA damage is currently unclear. METHODS AND RESULTS: To investigate this aspect a series of experiments were performed in which HUVEC were exposed to sub-lethal doses of the radio-mimetic compound Bleomycin (Bleo; 10 microg/ml) which generated free radicals (ROS) without significantly compromising cell survival. Remarkably, the application of a SS of 12 dyne/cm(2) did not protect endothelial cells but markedly accelerated apoptosis compared to controls kept in static culture and in the presence of Bleo. Experiments with the inducible nitric oxide synthase (iNOS) inhibitor GW274150 significantly reduced the SS-dependent apoptosis indicating that the production of NO was relevant for this effect. At molecular level, the ataxia-telangectasia-mutated (ATM) kinase, the homeodomain-interacting protein kinase-2 (HIPK2) and p53 were found activated along a pro-apoptotic signalling pathway while p21(waf1,cip1,sdi1) was prevented from its protective action. RNA interference experiments revealed that HIPK2 and p53 were both important for this process, however, only the forced expression p21(waf1,cip1,sdi1) fully restored the SS-dependent pro-survival function. CONCLUSIONS: This study provides the first evidence that, in the presence of genotoxic damage, laminar flow contributes to endothelial toxicity and death and identifies molecular targets potentially relevant in endothelial dysfunction and cardiovascular disease pathogenesis
Age and skill bias of trade liberalisation? : heterogeneous employment effects of EU Eastern Enlargement
This study analyses the 2004 Eastern Enlargement to the European Union to
obtain evidence on the employment effects of an increase in trade liberalisation. The
Enlargement is thought to generate a trade-induced demand shock with no (or only
limited) supply effects. Besides the variation over time induced by the Enlargement,
identification of the effects is based on a Melitz (2003) type productivity term to
differentiate firms by the extent of exposure to the demand shock. The idea is that the
effects of the demand shock should be driven by differences in firm-level productivity
from the period before the new member countries actually entered the EU. German
linked employer-employee data allow to observe the relation of initial establishment
productivity with employment changes over a long panel from 1995 to 2009. The
estimates show that the Enlargement had a negative effect on establishment-level
employment growth, which is driven by increased worker separations and increased
job destruction. Besides the overall employment effect, the study focuses on effect
heterogeneity across age and skill groups of the workforce. These estimates point to a
skill bias in the effect of the Enlargement that disadvantages low- and medium-skilled
workers in terms of higher worker separation and job destruction. In addition, lowskilled
workers suffer fewer accessions by firms, where against medium-skilled workers
enjoy increased accessions and creation of new jobs. Besides this indication for a skill
bias, there are no clear indications that point to an age bias in the employment effect
of the Eastern Enlargement
Targeting Hypoxia in Cancer Cells by Restoring Homeodomain Interacting Protein-Kinase 2 and p53 Activity and Suppressing HIF-1α
BACKGROUND:The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1alpha (HIF-1alpha) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1alpha, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance. METHODOLOGY/PRINCIPAL FINDINGS:Upon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1alpha expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1alpha promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1alpha promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes. CONCLUSIONS/SIGNIFICANCE:We show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment
Exporting and labor demand : micro-level evidence from Germany
It is widely believed that globalization affcts the extent of employment and
wage responses to economic shocks. To provide evidence for this, we analyze
the effect of firms' exporting behavior on the elasticity of labor demand. Using
rich, German administrative linked employer-employee panel data from 1996
to 2008, we explicitly control for self-selection into exporting and endogeneity
concerns. In line with our theoretical model, we find that exporting at both
the intensive and extensive margins significantly increases the (absolute value
of the) unconditional own-wage labor demand elasticity. This is not only true
for the average worker, but also for different skill groups. For the median
firm, the elasticity is three-quarters higher when comparing exporting to nonexporting
firms
Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients — the randomized, EU-wide, placebo-controlled, phase II study design of IXION
Background: More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods: IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (>= 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4-6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 x 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion: With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for
Efficient and accurate modeling of electron photoemission in nanostructures with TDDFT
We derive and extend the time-dependent surface-flux method introduced in [L. Tao, A. Scrinzi, New J. Phys. 14, 013021 (2012)] within a time-dependent density-functional theory (TDDFT) formalism and use it to calculate photoelectron spectra and angular distributions of atoms and molecules when excited by laser pulses. We present other, existing computational TDDFT methods that are suitable for the calculation of electron emission in compact spatial regions, and compare their results. We illustrate the performance of the new method by simulating strong-field ionization of C60 fullerene and discuss final state effects in the orbital reconstruction of planar organic molecules
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