Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.

The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.

Synthesis, Crystal Structure, and Photocatalytic Properties of Two Isoreticular Ce(IV)-MOFs with an Infinite Rod-Shaped Inorganic Building Unit.

The use of the V-shaped linker molecules 4,4'-oxydibenzoic acid (H2ODB) and 4,4'-carbonyldibenzoic acid (H2CDB) led to the discovery of two isoreticular Ce(IV)-based metal-organic frameworks (MOFs) of composition [CeO(H2O)(L)], L = ODB2-, CDB2-, denoted CAU-58 (CAU = Christian-Albrechts-University). The recently developed Ce-MOF synthesis approach in acetonitrile as the solvent proved effective in accessing Ce(IV)-MOF structures with infinite rod-shaped inorganic building units (IBUs) and circumventing the formation of the predominantly observed hexanuclear [Ce6O8] cluster. For the structure determination of the isoreticular MOFs, three-dimensional electron diffraction (3D ED) and powder X-ray diffraction (PXRD) data were used in combination with density functional theory (DFT) calculations. [CeO(H2O)(CDB)] shows reversible H2O adsorption by stirring in water and thermal treatment at 190 °C, which leads to a unit cell volume change of 11%. The MOFs feature high thermal stabilities (T > 290 °C), which exceed those of most Ce(IV)-MOFs and can be attributed to the infinite rod-shaped IBU. Surface and bulk oxidation states of the cerium ions were analyzed via X-ray photoelectron spectroscopy (XPS) and X-ray absorption near-edge spectroscopy (XANES). While Ce(III) ions are observed by the highly surface-sensitive XPS method, the bulk material contains predominantly Ce(IV) ions according to XANES. Application of the MOFs as catalysts for the catalytic degradation of methyl orange in aqueous solutions was also studied. While degradation activity for both MOFs was observed, only CAU-58-ODB revealed enhanced photocatalytic activity under ultraviolet (UV) light. The photocatalytic mechanism likely involves a ligand-to-metal charge transfer (LMCT) from the linkers to the Ce(IV) centers. Analyses by XANES and inductively coupled plasma-optical emission spectroscopy (ICP-OES) demonstrate that leaching of Cerium ions as well as partial reduction of Ce(IV) to Ce(III) takes place during catalysis. At the same time, PXRD data confirm the structural stability of the remaining MOF catalysts.

Discovery and In Situ Crystallization Studies of Cerium-Based Metal-Organic Frameworks with V-Shaped Linker Molecules.

We report the discovery and characterization of two porous Ce(III)-based metal-organic frameworks (MOFs) with the V-shaped linker molecules 4,4'-sulfonyldibenzoate (SDB2-) and 4,4'-(hexafluoroisopropylidene)bis(benzoate) (hfipbb2-). The compounds of framework composition [Ce2(H2O)(SDB)3] (1) and [Ce2(hfipbb)3] (2) were obtained by using a synthetic approach in acetonitrile that we recently established. Structure determination of 1 was accomplished from 3D electron diffraction (3D ED) data, while 2 could be refined against powder X-ray diffraction (PXRD) data using the crystal structure of an isostructural La-MOF as the starting model. Their framework structures consist of chain-like inorganic building units (IBUs) or hybrid-BUs that are interconnected by the V-shaped linker molecules to form framework structures with channel-type pores. The composition of both compounds was confirmed by PXRD, elemental analysis, as well as NMR and IR spectroscopy. Interestingly, despite the use of (NH4)2[CeIV(NO3)6] in the synthesis, cerium ions in both MOFs occur exclusively in the + III oxidation state as determined by X-ray absorption near edge structure (XANES) and X-ray photoelectron spectroscopy (XPS). Thermal analyses reveal remarkably high thermal stabilities of ≥400 °C for the MOFs. Initial N2 sorption measurements revealed the peculiar sorption behavior of 2 which prompted a deeper investigation by Ar and CO2 sorption experiments. The combination with nonlocal density functional theory (NL-DFT) calculations adds to the understanding of the nature of the different pore diameters in 2. An extensive quasi-simultaneous in situ XANES/XRD investigation was carried out to unveil the formation of Ce-MOFs during the solvothermal syntheses in acetonitrile. The crystallization of the two Ce(III)-MOFs presented herein as well as two previously reported Ce(IV)-MOFs, all obtained by a similar synthetic approach, were studied. While the XRD patterns show time-dependent MOF crystallization, the XANES data reveal the presence of Ce(III) intermediates and their subsequent conversion to the MOFs. The addition of acetic acid in combination with the V-shaped linker molecule was identified as the crucial factor for the formation of the crystalline Ce(III/IV)-MOFs.

The open toolbox for behavioral research.

In this work, we describe a new open-source MATLAB toolbox for the control of behavioral experiments. The toolbox caters to very different types of experiments in different species, and with different underlying hardware. Typical examples are operant chambers in animals, with or without neurophysiology, behavioral experiments in human subjects, and neurophysiological recordings in humans such as EEG and fMRI. In addition, the toolbox supports communication via Ethernet to either control and monitor one or several experimental setups remotely or to implement distributed paradigms across different computers. This flexibility is possible, since the toolbox supports a wide range of hardware, some of which is custom developments. An example is a fast network-based digital-IO device for the communication with experimental hardware such as feeders or triggers in neurophysiological setups. We also included functions for online video analysis allowing paradigms to be contingent on responses to a screen, the head movement of a bird in an operant chamber, or the physical location of an animal in an open arena. While the toolbox is well tested and many components of it have been in use for many years, we do not see it as a finished product but rather a continuing development with a focus on easy extendibility and customization.

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis.

BACKGROUND & AIMS: In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice. METHODS: The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n = 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMOΔhepa) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1Δhepa) mice. RESULTS: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMOΔhepa livers was rescued after deleting Keap1. As a consequence, NEMOΔhepa/KEAP1Δhepa livers showed reduced apoptosis compared to NEMOΔhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMOΔhepa/KEAP1Δhepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. CONCLUSIONS: NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis. LAY SUMMARY: The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer.

The DA-antagonist Tiapride affects context-related extinction learning in a predictive learning task, but not initial forming of associations, or renewal.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

Reaction Kinetics of Green Leaf Volatiles with Sulfate, Hydroxyl, and Nitrate Radicals in Tropospheric Aqueous Phase.

Green plants exposed to abiotic or biotic stress release C-5 and C-6 unsaturated oxygenated hydrocarbons called Green Leaf Volatiles (GLVs). GLVs partition into tropospheric waters and react to form secondary organic aerosol (SOA). We explored the kinetics of aqueous-phase reactions of 1-penten-3-ol (PENTOL), (Z)-2-hexen-1-ol (HEXOL), and (E)-2-hexen-1-al (HEXAL) with SO4•-, •OH, and NO3•. At 298 K, the rate constants for reactions of PENTOL, HEXOL, and HEXAL with SO4•- were, respectively, (9.4 ± 1.0) × 108 L mol-1 s-1, (2.5 ± 0.3) × 109 L mol-1 s-1, and (4.8 ± 0.2) × 108 L mol-1 s-1; with •OH - (6.3 ± 0.1) × 109 L mol-1 s-1, (6.7 ± 0.3) × 109 L mol-1 s-1, and (4.8 ± 0.3) × 109 L mol-1 s-1; and with NO3• - (1.5 ± 0.15) × 108 L mol-1 s-1, (8.4 ± 2.3) × 108 L mol-1 s-1, and (3.0 ± 0.7) × 107 L mol-1 s-1. The rate constants increased weakly with temperatures ranging from 278 to 318 K. The diffusional limitations of the rate constants appeared significant only for the GLV-•OH reactions. The aqueous-phase reactions appeared negligible in deliquescent aerosol and haze water but not in clouds and rains. The atmospheric lifetimes of GLVs decreased from many days to hours with increasing liquid water content and radicals' concentration.

MyD88-dependent signaling in non-parenchymal cells promotes liver carcinogenesis.

In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-alcoholic steatohepatitis (NASH)-a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor κB essential modulator, Nemo; NemoΔhepa). NemoΔhepa; NemoΔhepa/MyD88-/- and NemoΔhepa/MyD88Δhepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (NemoΔhepa/MyD88-/-) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.

Myeloid cells require gp130 signaling for protective anti-inflammatory functions during sepsis.

Sepsis represents a major health problem worldwide because of high mortality rates and cost-intensive therapy. Immunomodulatory strategies as a means of controlling overshooting inflammatory responses during sepsis have thus far not been effective, and there is a general paucity of new therapies. Regulatory immune cells have been shown to play important roles in limiting systemic inflammation. However, the signals inducing a regulatory phenotype in myeloid cells during infection are unknown. Here, we report that myeloid cell-intrinsic glycoprotein 130 (gp130) signals constitute a critical element for immune homeostasis during polymicrobial sepsis. We identify an essential role for gp130 signaling in myeloid cells during M2 macrophage polarization in vitro and in vivo. Myeloid cell-specific deletion of gp130 signaling leads to a defective M2 macrophage polarization followed by exacerbated inflammatory responses and increased mortality during sepsis. These data provide new insights into the molecular basis of M1 and M2 phenotypic dichotomy and identify gp130 as a key regulator of immune homeostasis during sepsis. Our study highlights the Janus-faced role of IL-6 family cytokines during inflammation, which may explain the failure of IL-6-targeted anti-inflammatory approaches in the treatment of sepsis.-Sackett, S. D., Otto, T., Mohs, A., Sander, L. E., Strauch, S., Streetz, K. L., Kroy, D. C., Trautwein, C. Myeloid cells require gp130 signaling for protective anti-inflammatory functions during sepsis.

Organosulfates in Ambient Aerosol: State of Knowledge and Future Research Directions on Formation, Abundance, Fate, and Importance.

Organosulfates (OSs), also referred to as organic sulfate esters, are well-known and ubiquitous constituents of atmospheric aerosol particles. Commonly, they are assumed to form upon mixing of air masses of biogenic and anthropogenic origin, that is, through multiphase reactions between organic compounds and acidic sulfate particles. However, in contrast to this simplified picture, recent studies suggest that OSs may also originate from purely anthropogenic precursors or even directly from biomass and fossil fuel burning. Moreover, besides classical OS formation pathways, several alternative routes have been discovered, suggesting that OS formation possibly occurs through a wider variety of formation mechanisms in the atmosphere than initially expected. During the past decade, OSs have reached a constantly growing attention within the atmospheric science community with evermore studies reporting on large numbers of OS species in ambient aerosol. Nonetheless, estimates on OS concentrations and implications on atmospheric physicochemical processes are still connected to large uncertainties, calling for combined field, laboratory, and modeling studies. In this Critical Review, we summarize the current state of knowledge in atmospheric OS research, discuss unresolved questions, and outline future research needs, also in view of reductions of anthropogenic sulfur dioxide (SO2) emissions. Particularly, we focus on (1) field measurements of OSs and measurement techniques, (2) formation pathways of OSs and their atmospheric relevance, (3) transformation, reactivity, and fate of OSs in atmospheric particles, and (4) modeling efforts of OS formation and their global abundance.

OH radicals reactivity towards phenol-related pollutants in water: temperature dependence of the rate constants and novel insights into the [OH-phenol]˙ adduct formation.

Substituted phenols are known to readily react with the hydroxyl radical (OH˙), which is the most powerful atmospheric oxidant and is also most often used in advanced oxidation processes (AOP) for wastewater treatment. We report temperature-dependent (278.15-318.15 K) second order kinetic rate constants for the aqueous-phase reactions of OH˙ with phenol and four substituted phenols: catechol, phloroglucinol, pyrogallol and 3-methylcatechol, with the last two measured for the first time. The constructed Hammett plots for mono- and di-substituted phenols have the potential to be further applied for predicting the reaction rate constants of other substituted phenols at 298.15 K. This will significantly facilitate the optimization of AOP and improve the predictive capabilities of atmospheric multiphase models in the future. Moreover, an advancement in the understanding of the underlying mechanism, i.e. OH˙ addition to the aromatic ring is made by theoretical calculations at the M06-2X level. We demonstrate that the position of substituents on the aromatic ring is important for the [OH-phenol]˙ adduct formation, which is supported by the experiment and theoretical calculations. Adjacent and nonadjacent electron donor/acceptor substituents differently impact the interplay between the activation energy and entropy. We also show that explicit solvation has to be accounted for in theoretical models in order to explicitly describe the formation of the transition state.

Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit.

MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.

Bulk Organic Aerosol Analysis by Proton-Transfer-Reaction Mass Spectrometry: An Improved Methodology for the Determination of Total Organic Mass, O:C and H:C Elemental Ratios, and the Average Molecular Formula.

We have recently shown in this journal (Müller et al. Anal. Chem. 2017 , 89 , 10889 - 10897 ) how a proton-transfer-reaction mass spectrometry (PTR-MS) analyzer measured particulate organic matter in urban atmospheres using the "Chemical Analysis of Aerosol Online" (CHARON) inlet. Our initial CHARON studies did not take into account fragmentation of protonated analyte molecules, which introduced a small but significant negative bias in the determination of bulk organic aerosol parameters. Herein, we studied the ionic fragmentation of 26 oxidized organic compounds typically found in atmospheric particles. This allowed us to derive a correction algorithm for the determination of the bulk organic mass concentration, mOA, the bulk-average hydrogen-to-carbon ratio, (H:C)bulk, the bulk-average oxygen-to-carbon ratio, (O:C)bulk, and the bulk-average molecular formula, MFbulk. The correction algorithm was validated against AMS data using two sets of published data. Finally, we determined MFbulk of particles generated from the reaction of α-pinene and ozone and compared and discussed the results in relation to the literature.

Aqueous-Phase Oxidation of cis-ß-Isoprene Epoxydiol by Hydroxyl Radicals and Its Impact on Atmospheric Isoprene Processing.

Isoprene epoxydiols are well-known intermediates of the isoprene oxidation in the gas phase under pristine conditions. According to their Henry's Law constants, they are well water-soluble and will undergo a phase transfer to the tropospheric aqueous phase to be further processed there. In the present study, the aqueous-phase oxidation by hydroxyl radicals (OH) of the isomer cis-ß-isoprene epoxydiol (cis-ß-IEPOX) was investigated with regards to its kinetics and reaction product distribution. For the reaction of cis-ß-IEPOX with hydroxyl radicals, a second-order rate constant of (1.4 ± 0.1) × 109 L mol-1 s-1 was determined at 298 K. Short chain carbonyls, such as glycolaldehyde with a maximum molar fraction of 6.9%, hydroxyacetone (7.4%), methylglyoxal (10.3%), and glyoxal (6.6%), as well as acetic acid (13.9%), were observed as major oxidation products. A total molar recovery of 75% was obtained in the oxidation experiments. The overall contribution of the aqueous-phase oxidation of cis-ß-IEPOX was estimated to range from 29.7 to 21.3% to the atmospheric processing depending on the scenario.

Kinetic and Theoretical Study of the Atmospheric Aqueous-Phase Reactions of OH Radicals with Methoxyphenolic Compounds.

Methoxyphenols, which are emitted through biomass burning, are an important species in atmospheric chemistry. In the present study, temperature-dependent aqueous-phase OH radical reactions of six methoxyphenols and two related phenols have been investigated through laser flash photolysis and the density functional theory. The rate constants obtained were in a range of (1.1-1.9) × 1010 L mol-1 s-1 with k(3-MC) > k(Cre) ≈ k(Syr) ≈ k(MEP) > k(Res) > k(3-MP) > k(2-EP) ≈ k(2-MP). We derived the parameters of these reactions from the obtained T-dependent rate constants and found a mean Arrhenius activation energy of 16.9 kJ mol-1. The diffusion rate constants were calculated for each case and compared to the measured ones. Generally, the rate constants are found to be close to fully diffusion-controlled (kdiff = (1.4-1.5) × 1010 L mol-1 s-1 for all reactions). A structure-function relationship was established through the measurement result, which could be used for predicting unknown rate constants of other phenolic compounds. All of these findings are expected to enhance the predictive capabilities of models, such as the chemical aqueous-phase radical mechanism.

Aqueous-Phase Oxidation of Terpene-Derived Acids by Atmospherically Relevant Radicals.

Terpene-derived acids formed through the atmospheric gas-phase oxidation of terpenes are able to efficiently undergo a phase transfer into the aqueous phase. The subsequent aqueous-phase oxidation of such compounds has not been intensely studied. Accordingly, the aqueous-phase second-order rate constants of the oxidation reactions of cis-pinonic acid (CPA) and (+)-camphoric acid (+CA) with hydroxyl radicals (•OH), nitrate radicals (NO3•), and sulfate radicals (SO4•-) were investigated as a function of temperature and pH in the present study. For CPA and +CA the following •OH reaction rate constants at T = 298 K are determined: ksecond(CPA, pH<2) = (2.8 ± 0.1) × 109 L mol-1 s-1, ksecond(CPA, pH>8) = (2.7 ± 0.3) × 109 L mol-1 s-1, ksecond(+CA, pH<2) = (2.1 ± 0.1) × 109 L mol-1 s-1, ksecond(+CA, pH=5.3) = (2.7 ± 0.3) × 109 L mol-1 s-1, ksecond(+CA, pH>8) = (2.7 ± 0.1) × 109 L mol-1 s-1. In order to assess the atmospheric impact of the aqueous-phase oxidation of such compounds, atmospheric aqueous-phase lifetimes were calculated for two model scenarios based on CAPRAM 3.0i. The aqueous-phase oxidation under remote conditions emerges to be the most favored pathway with lifetimes of 5 ± 1 h.

The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.

The Myc protein suppresses the transcription of several cyclin-dependent kinase inhibitors (CKIs) via binding to Miz1; whether this interaction is important for Myc's ability to induce or maintain tumorigenesis is not known. Here we show that the oncogenic potential of a point mutant of Myc (MycV394D) that is selectively deficient in binding to Miz1 is greatly attenuated. Binding of Myc to Miz1 is continuously required to repress CKI expression and inhibit accumulation of trimethylated histone H3 at Lys 9 (H3K9triMe), a hallmark of cellular senescence, in T-cell lymphomas. Lymphomas that arise express high amounts of transforming growth factor beta-2 (TGFbeta-2) and TGFbeta-3. Upon Myc suppression, TGFbeta signaling is required to induce CKI expression and cellular senescence and suppress tumor recurrence. Binding of Myc to Miz1 is required to antagonize growth suppression and induction of senescence by TGFbeta. We demonstrate that, since lymphomas express high levels of TGFbeta, they are poised to elicit an autocrine program of senescence upon Myc inactivation, demonstrating that TGFbeta is a key factor that establishes oncogene addiction of T-cell lymphomas.

The role of eye fixation in memory enhancement under stress - An eye tracking study.

In a stressful situation, attention is shifted to potentially relevant stimuli. Recent studies from our laboratory revealed that participants stressed perform superior in a recognition task involving objects of the stressful episode. In order to characterize the role of a stress induced alteration in visual exploration, the present study investigated whether participants experiencing a laboratory social stress situation differ in their fixation from participants of a control group. Further, we aimed at shedding light on the relation of fixation behaviour with obtained memory measures. We randomly assigned 32 male and 31 female participants to a control or a stress condition consisting of the Trier Social Stress Test (TSST), a public speaking paradigm causing social evaluative threat. In an established 'friendly' control condition (f-TSST) participants talk to a friendly committee. During both conditions, the committee members used ten office items (central objects) while another ten objects were present without being used (peripheral objects). Participants wore eye tracking glasses recording their fixations. On the next day, participants performed free recall and recognition tasks involving the objects present the day before. Stressed participants showed enhanced memory for central objects, accompanied by longer fixation times and larger fixation amounts on these objects. Contrasting this, fixation towards the committee faces showed the reversed pattern; here, control participants exhibited longer fixations. Fixation indices and memory measures were, however, not correlated with each other. Psychosocial stress is associated with altered fixation behaviour. Longer fixation on objects related to the stressful situation may reflect enhanced encoding, whereas diminished face fixation suggests gaze avoidance of aversive, socially threatening stimuli. Modified visual exploration should be considered in future stress research, in particular when focussing on memory for a stressful episode.

Tropospheric Aqueous-Phase Oxidation of Isoprene-Derived Dihydroxycarbonyl Compounds.

The dihydroxycarbonyls 3,4-dihydroxy-2-butanone (DHBO) and 2,3-dihydroxy-2-methylpropanal (DHMP) formed from isoprene oxidation products in the atmospheric gas phase under low-NO conditions can be expected to form aqSOA in the tropospheric aqueous phase because of their solubility. In the present study, DHBO and DHMP were investigated concerning their radical-driven aqueous-phase oxidation reaction kinetics. For DHBO and DHMP the following rate constants at 298 K are reported: k(OH + DHBO) = (1.0 ± 0.1) × 109 L mol-1 s-1, k(NO3 + DHBO) = (2.6 ± 1.6) × 106 L mol-1 s-1, k(SO4-+ DHBO) = (2.3 ± 0.2) × 107 L mol-1 s-1, k(OH + DHMP) = (1.2 ± 0.1) × 109 L mol-1 s-1, k (NO3 + DHMP) = (7.9 ± 0.7) × 106 L mol-1 s-1, k(SO4- + DHMP) = (3.3 ± 0.2) × 107 L mol-1 s-1, together with their respective temperature dependences. The product studies of both DHBO and DHMP revealed hydroxydicarbonyls, short chain carbonyls, and carboxylic acids, such as hydroxyacetone, methylglyoxal, and lactic and pyruvic acid as oxidation products with single yields up to 25%. The achieved carbon balance was 75% for DHBO and 67% for DHMP. An aqueous-phase oxidation scheme for both DHBO and DHMP was developed on the basis of the experimental findings to show their potential to contribute to the aqSOA formation. It can be expected that the main contribution to aqSOA occurs via acid formation while other short-chain oxidation products are expected to back-partition into the gas phase to undergo further oxidation there.

Up to 27-years clinical long-term results of chairside Cerec 1 CAD/CAM inlays and onlays.

The objective of this follow-up study was to examine the performance of Cerec 1 inlays and onlays in terms of clinical quality over a mean functional period of 25 years. Out of 200 Cerec 1 inlays and onlays placed consecutively in 108 patients in a private practice between 1989 and early 1991, 141 restorations could be reevaluated in 65 patients after up to 26 years and 10 months. All ceramic inlays and onlays had been generated chairside using the Cerec 1 method, and had been seated adhesively using bonding composite. At follow-up examinations, the restorations were classified based on modified United States Public Health Service (USPHS) criteria. According to the Kaplan-Meier analysis, the success rate of Cerec 1 inlays and onlays dropped to 87.5% after up to 27 years. In 19 patients, a total of 23 failures were found. Of these failures, 78% were caused by either ceramic fractures (65%) or tooth fractures (13%). The reasons for the remaining failures were caries (18%), and endodontic problems (4%). Three-surface restorations had a significantly higher failure risk (P < 0.05) than one-, two-, and four-surface restorations, and restorations in premolars presented a lower failure risk than those in molars. The survival probability of 87.5% after up to 27 years of clinical service of Cerec 1 computer-assisted design/computer-assisted manufacturing (CAD/CAM) restorations made of Vita Mark I feldspathic ceramic proved to be highly acceptable in private practice.