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The donor-free silanimines tBu2Si=N-SiRtBu2 (R = tBu, Ph), which are prepared from tBu2ClSiN3 and NaSiRtBu2 at −78 ◦C inBu2O, decompose in benzene at room temperature with the formation of isobutene. Products of ene reactions of isobutene and tBu2Si=N-SiRtBu2 (R = tBu, Ph) are formed. X-Ray quality crystals of H2C=C(CH2SitBu2-NH-SiPhtBu2)2 (monoclinic, space group C2/c, Z = 4) were grown from a benzene solution at ambient temperature, whereas single crystals of H2C=C(CH2SitBu2-NH-SitBu3)2 (monoclinic, space group P21, Z = 2) were obtained by recrystallization from THF.
The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
Peroxisome proliferator-activated receptor γ (PPARγ) gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer is associated with impaired PPARγ expression. Considering that regulation of PPARγ expression during inflammation is largely unknown, we were interested in elucidating underlying mechanisms. To this end, we initiated an inflammatory response by exposing primary human macrophages to lipopolysaccharide (LPS) and observed a rapid decline of PPARγ1 expression. Because promoter activities were not affected by LPS, we focused on mRNA stability and noticed a decreased mRNA half-life. As RNA stability is often regulated via 3′-untranslated regions (UTRs), we analyzed the impact of the PPARγ-3′-UTR by reporter assays using specific constructs. LPS significantly reduced luciferase activity of the pGL3-PPARγ-3′-UTR, suggesting that PPARγ1 mRNA is destabilized. Deletion or mutation of a potential microRNA-27a/b (miR-27a/b) binding site within the 3′-UTR restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS exposure, partially reversed PPARγ1 mRNA decay, whereas miR-27b overexpression decreased PPARγ1 mRNA content. In addition, LPS further reduced this decay. The functional relevance of miR-27b-dependent PPARγ1 decrease was proven by inhibition or overexpression of miR-27b, which affected LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin (IL)-6. We provide evidence that LPS-induced miR-27b contributes to destabilization of PPARγ1 mRNA. Understanding molecular mechanisms decreasing PPARγ might help to better appreciate inflammatory diseases.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting distinct proinflammatory genes (e.g. Il-1β and IFN-γ). IL-8 is a member of the proinflammatory chemokine family that is important for various functions, such as mediating the adhesion of eosinophilic granulocytes onto endothelial cells. The influence of PPARδ activators on the expression of IL-8 in noninduced quiescent endothelial cells is unclear. Therefore, we explored the influence of PPARδ activators on the expression of IL-8 in nonstimulated endothelial cells. PPARδ agonists induce IL-8 expression in human umbilical vein endothelial cells. This induction is demonstrated at the level of both protein and mRNA expression. Transcriptional activation studies using IL-8 reporter gene constructs and DNA binding assays revealed that PPARδ agonists mediated their effects via an NFκB binding site. It is well known that IL-8 is also regulated by mRNA stability. To provide further evidence for this concept, we performed mRNA stability assays and found that PPARδ agonists induce the mRNA stability of IL-8. In addition, we showed that PPARδ agonists induce the phosphorylation of ERK1/2 and p38, which are known to be involved in the increase of mRNA stability. The inhibition of these MAPK signaling pathways resulted in a significant suppression of the induced IL-8 expression and the reduced mRNA stability. Therefore, our data provide the first evidence that PPARδ induces IL-8 expression in nonstimulated endothelial cells via transcriptional as well as posttranscriptional mechanisms.
Experience-dependent alterations in the human brain's white-matter microstructure occur in early adulthood, but it is unknown whether such plasticity extends throughout life. We used cognitive training, diffusion-tensor imaging (DTI), and structural MRI to investigate plasticity of the white-matter tracts that connect the left and right hemisphere of the frontal lobes. Over a period of about 180 days, 20 younger adults and 12 older adults trained for a total of one hundred and one 1-h sessions on a set of three working memory, three episodic memory, and six perceptual speed tasks. Control groups were assessed at pre- and post-test. Training affected several DTI metrics and increased the area of the anterior part of the corpus callosum. These alterations were of similar magnitude in younger and older adults. The findings indicate that experience-dependent plasticity of white-matter microstructure extends into old age and that disruptions of structural interhemispheric connectivity in old age, which are pronounced in aging, are modifiable by experience and amenable to treatment.
Human exposure to endocrine disruptors is well documented by biomonitoring data. However, this information is limited to few chemicals like bisphenol A or phthalate plasticizers. To account for so-far unidentified endocrine disruptors and potential mixture effects we employ bioassays to detect endocrine activity in foodstuff and consequently characterize the integrated exposure to endocrine active compounds. Recently, we reported a broad contamination of commercially available bottled water with estrogenic activity and presented evidence for the plastic packaging being a source of this contamination. In continuation of that work, we here compare different sample preparation methods to extract estrogen-like compounds from bottled water. These data demonstrate that inappropriate extraction methods and sample treatment may lead to false-negative results when testing water extracts in bioassays. Using an optimized sample preparation strategy, we furthermore present data on the estrogenic activity of bottled water from France, Germany, and Italy: eleven of the 18 analyzed water samples (61.1%) induced a significant estrogenic response in a bioassay employing a human carcinoma cell line (MCF7, E-Screen). The relative proliferative effects ranged from 19.8 to 50.2% corresponding to an estrogenic activity of 1.9-12.2 pg estradiol equivalents per liter bottled water. When comparing water of the same spring that is packed in glass or plastic bottles made of polyethylene terephthalate (PET), estrogenic activity is three times higher in water from plastic bottles. These data support the hypothesis that PET packaging materials are a source of estrogen-like compounds. Furthermore, the findings presented here conform to previous studies and indicate that the contamination of bottled water with endocrine disruptors is a transnational phenomenon.
ϕ-meson production in In–In collisions at Elab=158A GeV: Evidence for relics of a thermal phase
(2010)
Yields and transverse mass distributions of the ϕ-mesons reconstructed in the ϕ→μ+μ− channel in In+In collisions at Elab=158A GeV are calculated within an integrated Boltzmann+hydrodynamics hybrid approach based on the Ultrarelativistic Quantum Molecular Dynamics (UrQMD) transport model with an intermediate hydrodynamic stage. The analysis is performed for various centralities and a comparison with the corresponding NA60 data in the muon channel is presented. We find that the hybrid model, that embeds an intermediate locally equilibrated phase subsequently mapped into the transport dynamics according to thermal phase-space distributions, gives a good description of the experimental data, both in yield and slope. On the contrary, the pure transport model calculations tend to fail in catching the general properties of the ϕ meson production: not only the yield, but also the slope of the mT spectra, compare poorly with the experimental observations at top SPS energies.
We demonstrate that a Quark–Gluon Plasma (QGP) with a dilute admixture of heavy quarks has, in general, a lower speed of sound than a “pure” QGP without effects from heavy flavors. The change in the speed of sound is sensitive to the details of the theory, making the hydrodynamic response to “flavoring” a sensitive probe of the underlying microscopic dynamics. We suggest that this effect may be measured in ultrarelativistic heavy ion collisions by relating the event-by-event number of charm quarks to flow observables such as the average transverse momentum.
Inclusive transverse momentum spectra of primary charged particles in Pb–Pb collisions at √sNN=2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0–5% and 70–80% of the hadronic Pb–Pb cross section. The measured charged particle spectra in |η|<0.8 and 0.3<pT<20 GeV/c are compared to the expectation in pp collisions at the same sNN, scaled by the number of underlying nucleon–nucleon collisions. The comparison is expressed in terms of the nuclear modification factor RAA. The result indicates only weak medium effects (RAA≈0.7) in peripheral collisions. In central collisions, RAA reaches a minimum of about 0.14 at pT=6–7 GeV/c and increases significantly at larger pT. The measured suppression of high-pT particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb–Pb collisions at the LHC.
The first measurement of two-pion Bose–Einstein correlations in central Pb–Pb collisions at √sNN=2.76 TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.
The inclusive charged particle transverse momentum distribution is measured in proton–proton collisions at s=900 GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region (|η|<0.8) over the transverse momentum range 0.15<pT<10 GeV/c. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for |η|<0.8 is 〈pT〉INEL=0.483±0.001 (stat.)±0.007 (syst.) GeV/c and 〈pT〉NSD=0.489±0.001 (stat.)±0.007 (syst.) GeV/c, respectively. The data exhibit a slightly larger 〈pT〉 than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.
In this Letter we derive the gravity field equations by varying the action for an ultraviolet complete quantum gravity. Then we consider the case of a static source term and we determine an exact black hole solution. As a result we find a regular spacetime geometry: in place of the conventional curvature singularity extreme energy fluctuations of the gravitational field at small length scales provide an effective cosmological constant in a region locally described in terms of a de Sitter space. We show that the new metric coincides with the noncommutative geometry inspired Schwarzschild black hole. Indeed, we show that the ultraviolet complete quantum gravity, generated by ordinary matter is the dual theory of ordinary Einstein gravity coupled to a noncommutative smeared matter. In other words we obtain further insights about that quantum gravity mechanism which improves Einstein gravity in the vicinity of curvature singularities. This corroborates all the existing literature in the physics and phenomenology of noncommutative black holes.
In this Letter we study the radiation measured by an accelerated detector, coupled to a scalar field, in the presence of a fundamental minimal length. The latter is implemented by means of a modified momentum space Green's function. After calibrating the detector, we find that the net flux of field quanta is negligible, and that there is no Planckian spectrum. We discuss possible interpretations of this result, and we comment on experimental implications in heavy ion collisions and atomic systems.
Fuzziness at the horizon
(2010)
We study the stability of the noncommutative Schwarzschild black hole interior by analysing the propagation of a massless scalar field between the two horizons. We show that the spacetime fuzziness triggered by the field higher momenta can cure the classical exponential blue-shift divergence, suppressing the emergence of infinite energy density in a region nearby the Cauchy horizon.
In this Letter, we propose a new scenario emerging from the conjectured presence of a minimal length ℓ in the spacetime fabric, on the one side, and the existence of a new scale invariant, continuous mass spectrum, of un-particles on the other side. We introduce the concept of un-spectral dimension DU of a d-dimensional, euclidean (quantum) spacetime, as the spectral dimension measured by an “un-particle” probe. We find a general expression for the un-spectral dimension DU labelling different spacetime phases: a semi-classical phase, where ordinary spectral dimension gets contribution from the scaling dimension dU of the un-particle probe; a critical “Planckian phase”, where four-dimensional spacetime can be effectively considered two-dimensional when dU=1; a “Trans-Planckian phase”, which is accessible to un-particle probes only, where spacetime as we currently understand it looses its physical meaning.
This review critically analyzes the clinical data of patients with suspected kava hepatotoxicity and suggests recommendations for minimizing risk. Kava is a plant (Piper methysticum) of the pepper family Piperaceae, and its rhizome is used for traditional aqueous extracts in the South Pacific Islands and for commercial ethanolic and acetonic medicinal products as anxiolytic herbs in Western countries. A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions. Based on one positive reexposure test with the kava drug, it was indeed confirmed that kava is potentially hepatotoxic. In subsequent studies using a structured, quantitative and hepatotoxicity specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava ± co-medicated drugs and dietary supplements including herbal ones was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements comprizing herbal ones in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as additional causative factor. In conclusion, in a few individuals kava may be hepatotoxic due to overdose, prolonged treatment, comedication, and probably triggered by an unacceptable quality of the kava raw material; standardization is now required, minimizing thereby hepatotoxic risks.
ecently, pertussis has become a problem also in the adult population, with incidences even higher than in children. Pediatric health care workers (HCWs) are an important source of transmission, exposing very young and immunocompromised patients to an increased risk of potentially severe pertussis infections. Encouraging HCWs to get vaccinated can play a vital role in stopping the transmission of pertussis, thereby reducing institutional outbreaks.
In Germany, HCWs come up with all sorts of reasons for not getting pertussis vaccination. This study was meant to provide information in order to better understand the backgrounds of these attitudes.
A survey was conducted at the children's university hospital in Frankfurt, using an anonymous questionnaire. Survey results were used to design an intervention to increase the immunization rate of staff. Disappointingly, our efforts to increase the acceptance of the immunization program by providing information in advance were not yet satisfying.
Misconception about pertussis vaccination was prevalent especially among nursing staff. The main reasons for non-compliance included: unawareness of an own risk of infection, the belief that pertussis is not a serious illness, fear of side effects, the belief that the pertussis vaccine might trigger the pertussis disease itself, and skepticism about the efficacy of the pertussis vaccination.
With respect to nosocomial influenza infections, the welfare of patients is best served by high rates of staff immunity against influenza. However, data from the Centers of Disease Control (CDC) in the USA and the Robert Koch-Institute (RKI) in Germany indicate that most of health care workers (HCWs) choose not to be vaccinated. Under voluntary influenza immunization standards, institutional influenza outbreaks occur every flu season. The question about the legality of implementation mandatory flu vaccination for HCWs is an ongoing debate, which covers several different positions.
To characterize the attitudes of German HCWs toward mandatory influenza immunization, an anonymous questionnaire was offered to HCWs of the University Hospital in Frankfurt/Main / Germany. Our study showed that almost 70% of the respondents would accept mandatory influenza vaccination.
In our opinion an annual influenza vaccination should be required for HCWs who care for immunocompromised patients and residents in long-term care if there will be a failure of voluntary vaccination programs. An informed declination should be obtained from employees who decline vaccination and these HCWs ought to work in uncritical areas of patient care.
Rhinoliths are mineralised foreign bodies in the nasal cavity that are a chance finding at anterior rhinoscopy. Undiscovered, they grow appreciably in size and can cause a foul-smelling nasal discharge and breathing problems. Giant nasal stones are now a very rare occurrence, since improved diagnostic techniques, such as endoscopic/microscopic rhinoscopy, now make it possible to identify foreign bodies at an early stage of development. We report the case of a 37-year-old patient who, at the age of 5-6 years, introduced a foreign body, probably a stone, into his right nasal cavity. On presentation, he complained of difficulty in breathing through the right nostril that had persisted for the last 10 years. For the past four years a strong fetid smell from the nose had been apparent to those in his vicinity. Under general anaesthesia, the stone was removed in toto from the right nasal cavity. The possible genesis of the rhinolith is discussed, our case compared with those described in the literature, and possible differential diagnoses are considered.