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The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4–Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4–Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S. [ABSTRACT FROM AUTHOR]

The structural properties and magnetic anisotropy of Pt/Co/Pt trilayers grown on thermally oxidized (Si/SiO2) and naturally oxidized silicon (Si/Siox) are presented. Although similar substrates and identical preparation conditions are used distinct differences in the structural composition are found which stem from the Pt seed layer created via ion assisted sputtering. While for thermal oxidized Si a Pt/Co/Pt trilayer is formed, for systems grown on naturally oxidized Si a complex PtSi alloy formation within the seed layer is observed as a consequence of the high ion energies of ion assisted sputtering. The composition of the PtSi alloy varies along the growth direction with a low Si content at the interface to Co and the lattice constant is similar to bulk Pt. The latter provides a much higher magnetic interface anisotropy constant compared to Pt/Co/Pt on thermal oxidized Si of about 0.9 mJ/m2 which is comparable to the highest values found for MBE grown Co on single crystalline Pt(111). [ABSTRACT FROM AUTHOR]

After being extirpated from the St. Lawrence River in the 1960s, striped bass (Morone saxatilis) were reintroduced to the estuary in 2002 and by 2008, they were naturally reproducing. To document the habitat use and feeding ecology of this reintroduced population, we examined the gut contents of 333 larvae and juveniles. Samples were collected in four estuarine habitats in 2014: the upstream freshwater section (UP), the oligohaline (O-ETM) and the mesohaline (M-ETM) estuarine turbidity maximum zones, and the downstream polyhaline section (DOWN). In June, pelagic larvae developed in the UP and the O-ETM, feeding mainly on copepods such as Eurytemora affinis. The O-ETM exhibited better suitable feeding conditions compared to the UP, likely due to the presence of Bosmina sp. as a primary prey. After July, striped bass shifted to larger prey items, consuming mainly dipteran pupa in upstream littoral habitats and gammarids and mysids in downstream habitats. In the early summer, the UP provided a high-quality nursery habitat and as the season progressed, the smallest juveniles dispersed downstream and improved their feeding success by exploiting a new feeding niche. This observation suggests that being distributed throughout the estuary may increase the potential survival of striped bass early life stages. [ABSTRACT FROM AUTHOR]

The analysis of the abundance and distribution of the early life‐history stages of the western Baltic spring‐spawning herring population, spanning 23 yr, revealed that the abundance of yolk‐sac larvae was strongly spatially structured and significantly more abundant during the optimal temperature window for viable hatch of herring larvae (9°C to 13°C). The percentage of time encompassing this optimal temperature window exhibited a major contraction between 1995 and 2000 that may have contributed to reducing the supply of yolk‐sac larvae and ultimately contributed to reducing recruitment observed after 2000. Temperature also significantly influenced the abundance of preflexion and flexion larvae, defining dome‐shaped responses with maximum abundances observed between 10.27°C and 13.43°C and between 13.68°C and 18.53°C, respectively. The abundances of postflexion stage larvae were greatest at temperatures exceeding 14°C with no apparent decline in abundance at temperatures of up to 20°C. Temperature also played a significant role in influencing the abundance of larvae through its interaction with the abundance of the preceding developmental stage and provided evidence of stage‐specific temperature‐related mortality. There was also evidence of reduced survival during the preflexion–flexion transition in cohorts produced early in the season relative to those cohorts produced later. Although phenologically plastic species such as herring may be able to alter the dates of spawning, thus partially mitigating the effects of increasing rates of spring warming, constriction of the temperature windows for successful hatching and subsequent ontogenetic development may not be so easily mitigated by changes in phenology. [ABSTRACT FROM AUTHOR]

The Nordic krill Meganyctiphanes norvegica and Arctic krill Thysanoessa raschii both dominate the krill community within the Estuary and Gulf of St. Lawrence system where they are central forage species for its pelagic ecosystem. We developed a species‐specific physiological individual based model that implements the critical physiological processes of growth, molting, and reproduction of female adults as responses to environmental forcing. Key innovations of our approach were the decoupling between the molting schedule and growth, as well as considering two distinct sources of prey (phytoplankton and mesozooplankton). Our simulation results revealed that the details of the feeding process were critical for an accurate representation of the production dynamics of adult individuals from both species. Their specific feeding preferences on phytoplankton and mesozooplankton resulted in distinct species‐specific phenological patterns that reproduced observations. The present study highlights the importance of detailed knowledge of diet and feeding behavior of krill species to improve our understanding of population responses in a rapidly changing environment. [ABSTRACT FROM AUTHOR]

Different krill species have a pivotal position in many marine food webs by both preying upon several trophic levels and being forage species for consumers. Within these food webs, different krill species coexist, though it remains unclear what mechanisms allow for the coexistence, for instance, of northern krill species in subarctic environments. Here, we hypothesize that the stable coexistence of sympatric krill species is based on trophic niche partitioning related to seasonal trade‐offs between their respective food preferences, their energy needs, and prey availability. To test our hypothesis, we analyzed the diets, feeding selectivity, and lipid composition of three coexisting northern krill species (Meganyctiphanes norvegica, Thysanoessa inermis, and Thysanoessa raschii) throughout 1 yr using a multimarker approach. We assessed lipid classes, fatty acids, and stable isotope signatures of krill and potential food sources (27 groups, from phytoplankton to lipid‐rich copepods) to elucidate seasonal variation of niche utilization. Results revealed strong trophic niche separation occurring at a very fine trophic scale (species level) throughout the year. The three krill species showed different degrees of food specialization rather than being purely opportunistic as classically proposed. Feeding on copepod prey was important to accumulate energy reserves for overwintering and subsequent rebuilding of energy reserves. Energy reserve utilization might reduce potential competition for the limited available resources, especially under low food conditions. [ABSTRACT FROM AUTHOR]

Weinvestigate the effect of strong interactions on the spectral properties of quantum wires with strong Rashba spin-orbit (SO) interaction in a magnetic field, using a combination of matrix product state and bosonization techniques. Quantum wires with strong Rashba SO interaction and magnetic field exhibit a partial gap in one-half of the conducting modes. Such systems have attracted wide-spread experimental and theoretical attention due to their unusual physical properties, among which are spin-dependent transport, or a topological superconducting phase when under the proximity effect of an s-wave superconductor. As a microscopic model for the quantum wire we study an extended Hubbard model with SO interaction and Zeeman field. We obtain spin resolved spectral densities from the real-time evolution of excitations, and calculate the phase diagram. We find that interactions increase the pseudo gap at k = 0 and thus also enhance the Majorana-supporting phase and stabilize the helical spin order. Furthermore, we calculate the optical conductivity and compare it with the low energy spiral Luttinger liquid result, obtained from field theoretical calculations. With interactions, the optical conductivity is dominated by an excotic excitation of a bound soliton-antisoliton pair known as a breather state. We visualize the oscillating motion of the breather state, which could provide the route to their experimental detection in e.g. cold atom experiments. [ABSTRACT FROM AUTHOR]

Preferential flow patterns in the subsurface are of great importance for the availability and the quality of water resources. However, knowledge of their spatial structure is still behind their importance, so that understanding the nature of preferential flow patterns is a major issue in subsurface hydrology. Comparing the statistics of river catchment sizes and spring discharges, we found that the morphology of preferential subsurface flow patterns is probably scale invariant and similar to that of dendritic river networks. This result is not limited to karstic aquifers where the occurrence of dendritic structures has been known at least qualitatively for a long time. The scale invariance even seems to be independent of the lithology of the aquifer. However, scale invariance of river patterns seems to be only limited by the continental scale, while scale invariance of subsurface flow patterns breaks down at much smaller scales. The upper limit of scale invariance in subsurface flow patterns is highly variable. We found a range from thousands of square kilometers for limestone aquifers down to less than 1 km2 in the weathered zone and debris accumulations of crystalline rocks. [ABSTRACT FROM AUTHOR]

Accumulating evidence supports the role of an aberrant transcriptome as a driver of metastatic potential. Deadenylation is a general regulatory node for post-transcriptional control by microRNAs and other determinants of RNA stability. Previously, we demonstrated that the CCR4-NOT scaffold component Cnot2 is an inherited metastasis susceptibility gene. In this study, using orthotopic metastasis assays and genetically engineered mouse models, we show that one of the enzymatic subunits of the CCR4-NOT complex, Cnot7, is also a metastasis modifying gene. We demonstrate that higher expression of Cnot7 drives tumor cell autonomous metastatic potential, which requires its deadenylase activity. Furthermore, metastasis promotion by CNOT7 is dependent on interaction with CNOT1 and TOB1. CNOT7 ribonucleoprotein-immunoprecipitation (RIP) and integrated transcriptome wide analyses reveal that CNOT7-regulated transcripts are enriched for a tripartite 3’UTR motif bound by RNA-binding proteins known to complex with CNOT7, TOB1, and CNOT1. Collectively, our data support a model of CNOT7, TOB1, CNOT1, and RNA-binding proteins collectively exerting post-transcriptional control on a metastasis suppressive transcriptional program to drive tumor cell metastasis. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, the shortening and removal of the poly(A) tail (deadenylation) of cytoplasmic mRNA is a key event in regulated mRNA degradation. A major enzyme involved in deadenylation is the Ccr4-Not deadenylase complex, which can be recruited to its target mRNA by RNA-binding proteins or the miRNA repression complex. In addition to six non-catalytic components, the complex contains two enzymatic subunits with ribonuclease activity: Ccr4 and Caf1 (Pop2). In vertebrates, each deadenylase subunit is encoded by two paralogues: Caf1, which can interact with the anti-proliferative protein BTG2, is encoded by CNOT7 and CNOT8, whereas Ccr4 is encoded by the highly similar genes CNOT6 and CNOT6L. Currently, it is unclear whether the catalytic subunits work co-operatively or whether the nuclease components have unique roles in deadenylation. We therefore developed a method to express and purify a minimal human BTG2-Caf1-Ccr4 nuclease sub-complex from bacterial cells. By using chemical inhibition and well-characterized inactivating amino acid substitutions, we demonstrate that the enzyme activities of Caf1 and Ccr4 are both required for deadenylation in vitro. These results indicate that Caf1 and Ccr4 cooperate in mRNA deadenylation and suggest that the enzyme activities of Caf1 and Ccr4 are regulated via allosteric interactions within the nuclease module. [ABSTRACT FROM AUTHOR]

Objective: Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study’s primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients. Design: This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥6 months with no history of virologic failure and whose HIV-1 RNA had been ≤75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1∶2 to continue current treatment or simplify to ABC/3TC+ATV. Methods: The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers. Results: After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2–4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3–4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. Conclusions: After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol. Trial Registration: ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734 [ABSTRACT FROM AUTHOR]

We report the first experimental demonstration of the parametric amplification of attosecond pulse trains at around 11 nm. The helium amplifier is driven by intense laser pulses and seeded by high-order harmonics pulses generated in a neon gas jet. Our measurements suggest that amplification takes place only if the seed pulse-trains are perfectly synchronized in time with the driving laser field in the amplifier. Varying the delay, we estimate the durations of the individual extreme ultraviolet pulses within the train to be on the order of 0.2 fs. Our results demonstrate that strong-field parametric amplification can be a suitable tool to amplify weak attosecond pulses from non-destructive pump-probe experiments and it is an important step towards designing amplifiers for realization of energetic XUV pulses with sub-femtosecond duration using compact lasers fitting in university laboratories. [ABSTRACT FROM AUTHOR]

The John's creek valley (Johnsbachtal) is presented as a long-term, interdisciplinary cooperation platform in upper Styria (Austrian Alps) that brings together the interests and knowledge of persons with different backgrounds (scientists, teachers, students, as well as local actors and the population) with the central aim to generate mutual benefit for all involved parties. It covers an area of around 65 km with elevations between 600 and 700 m in the valley to over 2,300 m in the summit regions. Annual mean temperature ranges from approximately 8 °C in the lower elevations of the valley to below 0 °C in the summit regions. Annual precipitation mounts to values of 1,500 mm and more than 1,800 mm in the lower elevations and summit regions, respectively. To allow for a long-term monitoring of the complex meteorological and hydrological conditions in the area, a hydroclimatological monitoring network has been installed that is described in detail in this paper. A special characteristic of the installed meteorological stations is that they cover a large range of altitudes and, therefore, allow to capture the gradients in meteorological variables induced by the complex Alpine topography. Furthermore, the hydroclimatological monitoring network in John's creek valley is largely independent of regular third-party project funding, and therefore, not temporarily limited in its existence. A number of catchment research activities that cover a variety of disciplines (e.g., climatology, hydrology, (hydro)geology, geomorphology) and that largely benefit from the hydroclimatological data recorded in John's creek valley are presented together with preliminary results. The latter include spatial distributions of meteorological and hydrological variables (e.g., precipitation, evapotranspiration and snowmelt) calculated for the test site using the hydrometeorological model AMUNDSEN. Furthermore, the results of hydrogeological investigations that have been carried out at the Etzbach spring are presented and discussed. [ABSTRACT FROM AUTHOR]

Background: Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. Methods: Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. Results: Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as ?H2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. Conclusion: In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent. [ABSTRACT FROM AUTHOR]

The human BTG/TOB protein family comprises six members (BTG1, BTG2/PC3/Tis21, BTG3/Ana, BTG4/PC3B, TOB1/Tob, and TOB2) that are characterised by a conserved BTG domain. This domain mediates interactions with the highly similar Caf1a (CNOT7) and Caf1b (CNOT8) catalytic subunits of the Ccr4-Not deadenylase complex. BTG/TOB proteins have antiproliferative activity: knockdown of BTG/TOB can result in increased cell proliferation, whereas over-expression of BTG/TOB leads to inhibition of cell cycle progression. It was unclear whether the interaction between BTG/TOB proteins and the Caf1a/Caf1b deadenylases is necessary for the anti-proliferative activity of BTG/TOB. To address this question, we further characterised surface-exposed amino acid residues of BTG2 and TOB1 that mediate the interaction with the Caf1a and Caf1b deadenylase enzymes. We then analysed the role of BTG2 and TOB1 in the regulation of cell proliferation, translation and mRNA abundance using a mutant that is no longer able to interact with the Caf1a/Caf1b deadenylases. We conclude that the anti-proliferative activity of BTG/TOB proteins is mediated through interactions with the Caf1a and Caf1b deadenylase enzymes. Furthermore, we show that the activity of BTG/TOB proteins in the regulation of mRNA abundance and translation is dependent on Caf1a/Caf1b, and does not appear to require other Ccr4-Not components, including the Ccr4a (CNOT6)/ Ccr4b (CNOT6L) deadenylases, or the non-catalytic subunits CNOT1 or CNOT3. [ABSTRACT FROM AUTHOR]

Background: Of the newer antiepileptic drugs, lamotrigine (LTG) and levetiracetam (LEV) are popular first choice drugs for epilepsy. The authors compared these drugs with regard to their efficacy and tolerability in the initial monotherapy for epilepsy.Methods: A randomised, open-label, controlled, parallel group, multicenter trial was conducted to test the superiority of the LEV arm over the LTG arm. The primary endpoint was the rate of seizure-free patients in the first 6 weeks (two-sided Fisher's exact test, α=0.05, intent-to-treat set). Furthermore, efficacy, tolerability and quality of life were evaluated. The authors included 409 patients aged ≥12 years with newly diagnosed focal or generalised epilepsy defined by either two or more unprovoked seizures or one first seizure with high risk for recurrence. Patients were titrated to 2000 mg/day of LEV or 200 mg/day of LTG reached on day 22 or 71, respectively. Two dose adjustments by 500/50 mg were allowed.Results: The proportions of seizure-free patients were 67.5% (LEV) versus 64.0% (LTG) 6 weeks after randomisation (p=0.47), and 45.2% (LEV) versus 47.8% (LTG) during the whole treatment period of 26 weeks. The HR (LEV vs. LTG) for seizure-free time was 0.86 (95% CI, 0.61 to 1.22). Adverse events occurred in 74.5% (LEV) versus 70.6% (LTG) of the patients (p=0.38). Adverse events associated with study discontinuation occurred in 17/204 (LEV) versus 8/201 (LTG) patients (p=0.07).Conclusions: There were no significant differences with regard to efficacy and tolerability of LEV and LTG in newly diagnosed focal and generalised epilepsy despite more rapid titration in the LEV arm.Clinical Trial Registration Number: ClinicalTrials.gov identifier NCT00242606. [ABSTRACT FROM AUTHOR]

The 7.8 eV nuclear isomer transition in 229thorium has been suggested as a clock transition in a new type of optical frequency standard. Here we discuss the construction of a 'solid-state nuclear clock' from thorium nuclei implanted into single crystals transparent in the vacuum ultraviolet range. We investigate crystal-induced line shifts and broadening effects for the specific system of calcium fluoride. At liquid nitrogen temperatures, the clock performance will be limited by decoherence due to magnetic coupling of the thorium nuclei to neighboring nuclear moments, ruling out the commonly used Rabi or Ramsey interrogation schemes. We propose clock stabilization based on a fluorescence spectroscopy method and present optimized operation parameters. Taking advantage of the large number of quantum oscillators under continuous interrogation, a fractional instability level of 10-19 might be reached within the solid-state approach. [ABSTRACT FROM AUTHOR]

This study aimed at describing changes in the stable isotopic composition of late copepodite stage V (CV) subarctic marine copepods (Calanus finmarchicus and C. hyperboreus) during overwintering non-feeding periods. Diapausing stage CVs sampled in deep waters of the Lower St. Lawrence Estuary (Québec, Canada) in late-September 2009 were monitored for 4 months under controlled laboratory conditions. CVs and newly moulted adults were analyzed for δ13C and δ15N signatures as well as lipid, carbon and nitrogen content. Lipids were extracted in half of the samples to compare δ13C of individuals with and without lipids and to evaluate the accuracy of mass balance correction models for δ13C under lipid influence. Lipid content generally decreased with time for both species, which was reflected in an increase of δ13C values of CVs but a constant δ13C in newly moulted adults. Accordingly, lipid extraction resulted in an increase of δ13C in CVs and adults. The mean δ13C signature of lipid-extracted individuals remained constant through the time for CVs of both species and for C. finmarchicus adults. δ15N signatures of individuals increased after lipid extraction, but this did not result in a constant value over time, suggesting that several endogenous metabolic processes affected nitrogen isotopic content. The accuracy of the mass balance model differed between species and stages, suggesting that lipid extraction should always be performed prior to applying mathematical corrections. [ABSTRACT FROM PUBLISHER]

The Ccr4-Not complex is one of the major deadenylase factors present in eukaryotic cells. This multisubunit protein complex is composed of at least seven stably associated subunits in mammalian cells including two enzymatic deadenylase subunits: one DEDD (Asp-Glu-Asp-Asp)-type deadenylase (either CNOT7/human Caf1/Caf1a or CNOT8/human Pop2/Caf1b/Calif) and one EEP (endonuclease-exonuclease- phosphatase)-type enzyme (either CNOT6/human Ccr4/Ccr4a or CNOT6L/human Ccr4-like/Ccr4b). Here, the role of the human Ccr4-Not complex in cytoplasmic deadenylation of mRNA is discussed, including the mechanism of its recruitment to mRNA and the role of the BTG/Tob proteins. [ABSTRACT FROM AUTHOR]

The aim of this work was to analyse the furan concentrations in coffee products targeted to adolescents and to estimate the health risk for those consumers by using the consumption data of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study (DONALD). Three different kinds of coffee beverages were analysed: 'coffee ready to drink' (i.e. industrially manufactured and packaged products available in cans or plastic cups), 'coffee instant' (i.e. soluble coffee in powder form) and 'coffee from coffee chains' (i.e. freshly prepared coffee sampled on-site). Furan was analysed according to the US Food and Drug Administration (USFDA) method using headspace-GC-MS and quantification with standard addition. The lowest furan concentrations were found within the category 'coffee instant', with an average of 4.6 µg kg−1, followed by the category 'coffee ready to drink', with an average of 41.3 µg kg−1, while the products from the coffee chains showed the highest concentrations, on average 100.5 µg kg−1. According to the obtained furan contents, it seems that the highest furan exposure for adolescents is generally given in the consumption of products within the category 'coffee from coffee chains', while the lowest is given in the category 'coffee instant'. Risk assessment based on the margin of exposure (MOE) approach showed that in different consumption scenarios except for consumers of instant coffee, the MOE lay below 10,000, a range that is judged to be of public health relevance. The lowest MOE was found for consumers in the age group 10–12 years (especially females) and for both sexes in the age group 16–18 years. [ABSTRACT FROM AUTHOR]

This article presents the modification and testing of an ADC-based thermometry bridge. The instrument under investigation is an Anton Paar MKT 50 Millikelvin Thermometer (developed at the IFE, TU-Graz) based on a precision analog-to-digital converter (ADC). During preliminary testing, it was found that the MKT 50 performs better than its declared uncertainty (1 mK equal to 1 ppm when using a 100 Ω PRT) and is comparable to thermometry resistance ratio bridges typically used in secondary thermometry laboratories (with typical uncertainties from 0.1 mK to 1 mK). The modifications to the original bridge were undertaken by the development team of the MKT 50 at the Graz University of Technology, Austria. Measurements and evaluation of the modified instruments were performed at the MIRS/UL-FE/LMK. For the MKT 50 to be used in thermometry laboratories as a reference unit, measuring parameters of the instrument had to be changed. During the first modification, the upper limit of the instrument range was decreased from 400 Ω to 133 Ω, this is a preferred range for standard platinum resistance thermometers (SPRTs). This also meant an increase in the measuring current from 0.5 mA to the more frequently used 1 mA. A modification of the programmable ADC control unit increased the resolution from 24 bit to 27 bit. By adding a switch, the use of an external standard resistor was enabled. After this stage of the modification, the first tests on the instrument were performed. The second stage was aimed at the removal of noise sources. The instrument was prepared in such a way that it only used two input channels, one connected to the SPRT and the other to the standard resistor. Also, the components of the ADC were upgraded to further reduce noise. The elimination of one input channel sped up measurements, making the PC software capable of taking several readings in a shorter time period. All tests were performed in laboratory conditions, where precision AC and DC resistance ratio bridges are typically used. The non-linearity was assessed by the use of an automated resistance bridge calibrator (RBC, Model RBC100), while the noise value was determined both from the standard deviation of RBC measurements as well as from comparison measurements of two standard resistors. All tests were repeated several times to assure confidence in the results. With its lowered range of 133 Ω and an increased resolution of 27 bit, the instrument non-linearity, its value below 2 μΩ, was comparable to primary resistance ratio bridges such as the ASL F900 or MI 6015T. However, the noise of the instrument remained relatively high at 4 μΩ. Since the modified MKT-50 is a much faster instrument than AC and DC bridges, averaging was used for true comparison. Measurements done with the modified MKT 50 were also averaged every 15 s (the time a classic resistance ratio bridge takes for one measurement). When measurements with the MKT-50 were averaged, the noise of measurements would be comparable to primary resistance ratio bridges. [ABSTRACT FROM AUTHOR]

This paper deals with estimation of fractal dimension of realizations of random fields. Numerical methods are based on analysis of variance of increments. It is proposed to study fractal properties with the use of a specific characteristic of randomfields called a 'variational dimension.' For a class of Gaussian fields with homogeneous increments the variational dimension converges to the Hausdorff dimension. Several examples are presented to illustrate that the concept of variational dimension can be used to construct effective computational methods. [ABSTRACT FROM AUTHOR]

The mammalian BTG/Tob family comprises six proteins (BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2), which regulate cell cycle progression in a variety of cell types. They are characterised by the conserved N-terminal domain spanning 104–106 amino acids. Recent biochemical and structural data indicate that the conserved BTG domain is a protein–protein interaction module, which is capable of binding to DNA-binding transcription factors as well as the paralogues CNOT7 (human Caf1/Caf1a) and CNOT8 (human Pop2/Calif/Caf1b), two deadenylase subunits of the Ccr4-Not complex. Consistent with this finding, several members of the BTG/Tob family are shown to be implicated in transcription in the nucleus and cytoplasmic mRNA deadenylation and turnover. The C-terminal regions are less conserved and appear to mediate protein–protein interactions that are unique to each family member. The human and mouse BTG/Tob proteins will be the focus of this review and structural aspects of BTG/Tob interactions with components of the Ccr4-Not complex, and the role of the BTG/Tob proteins in the regulation of gene expression, tumourigenesis and cancer will be discussed. J. Cell. Physiol. 222:66–72, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A concept of variational dimension is introduced for a random sequence with stationary increments. In the Gaussian case, the variational dimension in the limit coincides with the Hausdorff dimension of a proper random process. Applications of the concept are illustrated by examples of neurological data and network traffic analysis. [ABSTRACT FROM AUTHOR]

During a combined pilot-scale study, operating conditions were fixed for three different membrane configurations a multi tube, a hollow fibre and a flat sheet membrane type. Changes in activated sludge filterability were quantified depending on the membrane chambers, the permeate flux of extraction and the membrane chamber aeration. The aim of this study was to provide a better understanding of the interactions between MBR activated sludges and hydraulic circumstances depending on membrane configurations. Two mechanisms can be distinguished from this study: Due to practical arrangements, hydraulic conditions in each membrane unit are different, leading to different total suspended solids concentrations (TSS). These margins in TSS contents cause differences in filtration behaviour. The multi tube configuration did not affect the activated sludge filterability. The activated sludge filterability remained the same in spite of flux and air-lift velocity changes. The flat sheet and the hollow fibre configuration did affect the sludge filterability. The filterability improved significantly at high flux and at low air-lift velocity (from 20% to 90% of improvement). The TSS concentration phenomenon is likely to be responsible for the activated sludge filterability improvement. It might be due to floc structure modifications resulting in a better cake layer porosity. No correlations were found between SMP and filterability. [ABSTRACT FROM AUTHOR]

A low educational level and a poor socioeconomic status could be associated with increased risk for chronic diseases. The aim of the study was to evaluate the relationship between the educational level and cardiometabolic risk in adult patients with type 1 diabetes ( n = 437; age: 38.0 ± 10.4 years, duration of diabetes: 19.2 ± 11.1 years; x ± SD). Educational levels were classified as low [primary school, n = 56 (12.8%)], middle [high school, n = 251 (57.4%)] or high [university, n = 130 (29.7%)]. The prevalence rate of the metabolic syndrome proved to be higher in patients with low versus high educational levels (ATP-III criteria: 42.9 vs. 21.5%, P = 0.0006). Antihypertensive treatment and cardiovascular diseases were more prevalent in patients with low versus high educational level (46.4 vs. 26.2%, P = 0.01; 12.5 vs. 2.3%, P = 0.02; respectively). Overall glycemic control was worse in patients with low versus high educational level (HbAlc: 8.8 ± 1.6 vs. 7.9 ± 1.4%; P = 0.0006). Patients with low versus high educational level differed significantly regarding smoking habits (smokers: 28.6 vs. 11.6%; P = 0.01) and regular physical activity (5.4 vs. 33.1%; P = 0.0001). Higher prevalence rate of certain cardiometabolic risk factors was associated with low educational level in middle-aged type 1 diabetic patients with relatively long duration of diabetes; therefore, these patients should have priority when preventing cardiovascular complications. [ABSTRACT FROM AUTHOR]

Aim: To determine if therapeutic management programmes for type 2 diabetes that include self-monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non-insulin requiring patients. Methods: Multicentre, randomized, parallel-group trial. A total of 610 patients were randomized to SMBG or non-SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)–based regimen for 27 weeks. The primary efficacy end-point was the difference between groups in HbA1c at the end of observation. Results: A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non-SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non-SMBG group; between-group difference was 0.25% (95% CI: 0.06, 1.03; p = 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non-SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group. Conclusion: In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c. [ABSTRACT FROM AUTHOR]

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Using Monte Carlo simulation techniques, we look at statistical properties of two numerical methods (the extended counting method and the variance counting method) developed to estimate the Hausdorff dimension of a time series and applied to the fractional Brownian motion. [ABSTRACT FROM AUTHOR]

We present very fast algorithms for the exact computation of estimators for time series, based on complexity penalized log-likelihood or M-functions. The algorithms apply to a wide range of functionals with morphological constraints, in particular to Potts or Blake-Zisserman functionals. The latter are the discrete versions of the celebrated Mumford-Shah functionals. All such functionals contain model parameters. Our algorithms allow for optimization not only for each separate parameter, but even for all parameters simultaneously. This allows for the examination of the models in the sense of a family approach. The algorithms are accompanied by a series of illustrative examples from molecular biology. [ABSTRACT FROM AUTHOR]

Background: Once-daily (QD) ritonavir 100 mg-boosted fosamprenavir 1400 mg (FPV/r100) or atazanavir 300 mg (ATV/r100), plus tenofovir/emtricitabine (TDF/FTC) 300 mg/200 mg, have not been compared as initial antiretroviral treatment. To address this data gap, we conducted an openlabel, multicenter 48-week study (ALERT) in 106 antiretroviral-naïve, HIV-infected patients (median HIV-1 RNA 4.9 log10 copies/mL; CD4+ count 191 cells/mm³) randomly assigned to the FPV/r100 or ATV/r100 regimens. Results: At baseline, the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA (median, 4.9 log10 copies/mL [both]), CD4+ count (mean, 176 vs 205 cells/mm³). At week 48, intent-to-treat: missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 (HIV-1 RNA < 50 copies/mL: 75% (40/53) vs 83% (44/53), p = 0.34 [Cochran-Mantel-Haenszel test]); mean CD4+ count change-from-baseline: +170 vs +183 cells/mm³, p = 0.398 [Wilcoxon rank sum test]). Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar, although week 48 median fasting triglycerides were higher with FPV/r100 (150 vs 131 mg/dL). FPV/r100-treated patients experienced fewer treatment-related grade 2-4 adverse events (15% vs 57%), with differences driven by ATV-related hyperbilirubinemia. Three patients discontinued TDF/FTC because their GFR decreased to <50 mL/min. Conclusion: The all-QD regimens of FPV/r100 and ATV/r100, plus TDF/FTC, provided similar virologic, CD4+ response, and fasting total/LDL/HDL-cholesterol changes through 48 weeks. Fewer FPV/r100-treated patients experienced treatment-related grade 2-4 adverse events. [ABSTRACT FROM AUTHOR]

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The Ccr4-Not complex is a highly conserved regulator of mRNA metabolism. The transcription regulatory function of this complex in higher eukaryotes, however, is largely unexplored. Here we report that CNOT1, the large human subunit, represses the ligand-dependent transcriptional activation function of oestrogen receptor (ER) α. Promoter recruitment assays indicate that CNOT1 contains an intrinsic ability to mediate transcriptional repression. Furthermore, CNOT1 can interact with the ligand-binding domain of ERα in a hormone-dependent fashion and is recruited with other Ccr4-Not subunits to endogenous oestrogen-regulated promoters dependent on the presence of ligand. In addition, siRNA-mediated depletion of endogenous CNOT1 or other Ccr4-Not subunits in breast cancer cells results in deregulation of ERα target genes. Finally, CNOT1 interacts in a ligand-dependent manner with RXR and represses transcription mediated by several RXR heterodimers. These findings define a function for the human Ccr4-Not complex as a transcriptional repressor of nuclear receptor signalling that is relevant for the understanding of molecular pathways involved in cancer. [ABSTRACT FROM AUTHOR]

The hydrogeological effectiveness of fracture sets is determined and evaluated by the fuzzy c-mean and hierarchical clustering. These cluster analyses combine the geological spatial attributes and the hydraulic relevant attributes of fractures. Based on the results of the clustering the fracture set volumes are estimated. [ABSTRACT FROM AUTHOR]

Background. Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. Methods. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV- 1 RNA level by week 8, (2) an HIV-1 RNA rebound of ⩾1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. Results. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm³, respectively; 194 subjects with HIV-1 RNA data from ⩾8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. Conclusion. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used. [ABSTRACT FROM AUTHOR]

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