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Supplementary Methods and Figure from Cellular Targets of Gefitinib

Supplementary Table 2 from Cellular Targets of Gefitinib

Supplementary Table 1 from Cellular Targets of Gefitinib

Supplementary Methods from Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling

Targeted inhibition of protein kinases with small molecule drugs has evolved into a viable approach for anticancer therapy. However, the true selectivity of these therapeutic agents has remained unclear. Here, we used a proteomic method to profile the cellular targets of the clinical epidermal growth factor receptor kinase inhibitor gefitinib. Our data suggest alternative cellular modes of action for gefitinib and provide rationales for the development of related drugs.

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1–mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.

Supplementary Figure 1 from Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling

At the beginning of 2020 the Austrian palynologist, Reinhard Zetter, turned 65. This issue, composed of articles by his colleagues and some of his former students, is dedicated to him. Figure 1. Th...

The time of the Vesuvius eruption, which perished Pompeii, Herculaneum and surrounding areas in ad 79, was initially set on the 24–25 August, based on written contemporary documents of the ancient ...

The pollen spectra of air and surface soil samples from a rooftop (at 14 m) and from ground level (at 1.6 m) in the suburbs of Vienna (Austria) were compared. Two soil samples and two air s...

Cultural background is an important variable influencing neuropsychological performance. Multinational projects usually involve gathering data from participants from different countries and/or different cultures. Little is known about the influence of culture on neuropsychological testing results in children and especially in European children. The objectives of this study were to compare neuropsychological performance of children from six European countries (Belgium, Germany, Italy, The Netherlands, Poland and Spain) using a comprehensive neuropsychological battery and to apply a statistical procedure to reduce the influence of country/cultural differences in neuropsychological performance. As expected, the results demonstrated differences in neuropsychological performance among children of the six countries involved. Cultural differences remained after adjusting for other confounders related to neuropsychological execution, such as sex, type of delivery, maternal age, gestational age and maternal educational level. Differences between countries disappeared and influence of culture was considerably reduced when standardised scores by country and sex were used. These results highlight the need for developing specific procedures to compare neuropsychological performance among children from different cultures to be used in multicentre studies.

Bone mineralization can be influenced by genetic factors, hormonal status, nutrition, physical activity and body composition. The association of higher calcium (Ca) intake or Ca supplementation with better bone mineral density (BMD) remains controversial. Furthermore, it has been speculated that maintaining long-term adequate Ca intake rather than having a brief supplementation period is more effective. The aim of the study was to prospectively analyse the influence of adequate Ca intake on BMD at 7 years of age in European children.Data from the Childhood Obesity Project were analysed in a prospective longitudinal cohort trial. Dietary intake was recorded using 3-day food records at 4, 5 and 6 years of age. The probability of adequate intake (PA) of Ca was calculated following the American Institute of Medicine guidelines for individual assessments, with FAO, WHO and United Nations University joint expert consultation dietary recommendations. Children were categorised as having high Ca PA (PA95%) or not (PA95%). At 7 years, whole body (WB) and lumbar spine (LS) BMD were measured in the Spanish subsample by dual-energy x-ray absorptiometry. Internal BMD z-scores were calculated; BMD below -1 z-score were considered to indicate osteopenia, and BMD z-scores below -2, "low bone mineral density for age".BMD was measured in 179 children. Ca intake at 6 years was positively correlated with LS BMD at 7 years (R = 0.205, p = 0.030). A Ca increase of 100 mg/day explained 19.4% (p = 0.011) of the LS BMD z-score variation, modifying it by 0.089 (0.021, 0.157) units. Children with Ca PA95% at 5 and 6 or from 4 to 6 years of age showed higher BMD z-scores at the LS and WB levels than children with Ca PA95% (p 0.001 and p 0.05 for LS and WB BMD, respectively). Ca PA95% maintained over 2 years explained 26.3% of the LS BMD z-score variation (p 0.001), increasing it by 0.669 (0.202, 1.137). PA95% maintained over 3 years explained 24.9% of the LS BMD z-score variation, increasing it by 0.773 (0.282, 1.264). The effects of Ca adequacy on WB BMD were similar. Children with PA95% over 2 years had an Odds ratio of 13.84 and 12 for osteopenia at the LS and WB levels, respectively (p = 0.001).Long periods of adequate Ca intake in childhood increase BMD and reduce osteopenia risk. The Childhood Obesity Project clinical trial (CHOP) was registered at clinicaltrials.gov as NCT00338689.

Summary Background In European countries, suboptimal intake has been reported for several micronutrients (as calcium, iron, zinc, vitamin B12, D and folate) in both adulthood and childhood. No studies to date have prospectively compiled nutrient intake from healthy children in different European countries using the same methodology. Aim To describe the adequacy of micronutrient intake during the first eight years of life in children from 5 European countries. Methods Prospective observational trial analyzing data from the EU Childhood Obesity Project. Infants were enrolled within the first two months of life and were followed regularly to age 8 years. Dietary intake was collected periodically with 3-day food records. Nutrient intake adequacy was estimated for calcium, phosphorus, iron, zinc, magnesium, iodine, folate and vitamins B12, A and D, following the American Institute of Medicine (IOM) guidelines at group (prevalence of adequacy >80%) and individual (high probability of adequate intake >80% of the children) level; the assessment was based on the Estimated Average Requirements of nutrients of the FAO, WHO and United Nations University (FAO/WHO/UNU) or the IOM if FAO/WHO/UNU data were not available. Results Intake data were available for a decreasing number of children, from 904 at 3 months to 396 at 8 years. Iron, iodine, folate and vitamin D were inadequately consumed when assessing adequacy at group level; at individual-level less than 80% of the children showed high probability of adequate intake for iron, iodine, folate and zinc at all ages, and calcium from 12 months onwards. Conclusions Accurate dietary intake and adequacy assessment methodology in this prospective cohort of European children found iron, calcium, vitamin D, folate, iodine and zinc to be inadequately consumed in childhood, as described previously by epidemiologic studies. Further studies are needed to elucidate health consequences of these deficiencies. CHOP trial was registered at clinicaltrials.gov as NCT00338689 .

Wahrend der Arbeitszeit schnell auf dem Handy private Nachrichten abrufen, telefonisch einen Arzttermin vereinbaren, oder, weil gerade nichts Dringendes zu tun ist, am Dienstcomputer ein paar Einkaufe im Internet erledigen. Ist das heutzutage normal und deshalb erlaubt oder kann es — womoglich ohne vorherige Abmahnung — den Arbeitsplatz kosten? Wie ist die Rechtslage?

In recent years, online invoice trading has gained importance in providing SMEs with short-term financing. In this paper, we present first empirical evidence concerning the question whether the risk of payment difficulties is appropriately reflected in the pricing variables. To this end, we investigate predictors of default of online invoice trading platforms. We analyze both the probability of default and the loss rate and find that the interest rate, the duration and the percentage funded have good predictive power. Furthermore, we show that the pricing mechanism (auction vs. fixed prices) helps to explain defaults on online invoice trading platforms.

Adiposity and obesity result from the interaction of genetic variation and environmental factors from very early in life, possibly mediated by epigenetic processes. Few Epigenome-Wide-Association-Studies have identified DNA-methylation (DNAm) signatures associated with BMI and body composition in children. Body composition by Bio-Impedance-Analysis and genome-wide DNAm in whole blood were assessed in 374 pre-school children from four European countries. Associations were tested by linear regression adjusted for sex, age, centre, education, 6 WBC-proportions according to Houseman and 30 principal components derived from control probes. Specific DNAm variants were identified to be associated with BMI (212), fat-mass (230), fat-free-mass (120), fat-mass-index (24) and fat-free-mass-index (15). Probes in genes SNED1(IRE-BP1), KLHL6, WDR51A(POC1A), CYTH4-ELFN2, CFLAR, PRDM14, SOS1, ZNF643(ZFP69B), ST6GAL1, C3orf70, CILP2, MLLT4 and ncRNA LOC101929268 remained significantly associated after Bonferroni-correction of P-values. We provide novel evidence linking DNAm with (i) altered lipid and glucose metabolism, (ii) diabetes and (iii) body size and composition in children. Both common and specific epigenetic signatures among measures were also revealed. The causal direction with phenotypic measures and stability of DNAm variants throughout the life course remains unclear and longitudinal analysis in other populations is required. These findings give support for potential epigenetic programming of body composition and obesity.

The pollen content of the air in an office was assessed together with the dust on the floor and on the desktops as well as the pollen content outside of the building on rooftops and at ground level. The whole pollen spectrum was evaluated (35 different pollen types) with focus on the major aeroallergens. The air samples were measured with Hirst-type pollen traps and the dust samples were evaluated following guidelines in forensic palynology. The same time period was examined on four different sampling days: (1) during the winter as a reference day, (2) during the main pollination period of Betula , (3) during the main pollination period of Poaceae and (4) during the main pollination period of Ambrosia . Pollen concentrations were generally lower in indoor air than in outdoor air (except for the winter day), but showed associations with dust by containing non-seasonal pollen types as well as seasonal pollen. Staying indoors is recommended for pollen allergy sufferers, but does not grant the absence of pollen or the total avoidance of symptoms. Results indicate that persons concerned should keep in mind being confronted with pollen in certain amounts throughout the year indoors in built environment.

U ovome radu predstavljena je paleookolišna rekonstrukcija creta u blizini sela Blatuše, s naglaskom na promjene u strukturi i sastavu vegetacije, hidrološkoga režima i povijesti požara na području Banovine/Korduna tijekom posljednja dva tsućljeća. U svrhu paleookolišne interpretacije, napravljena je analiza akumuliranoga peluda, nepeludnih palinomorfa i pougljenjenih čestica. Upotrebom CONISS statističkoga modela mogu se razlučiti tri različite (pod)zone akumulacije: vegetacija „joha-bukva/hrastovi“ dominanira razdobljem od 2. stoljeća do sredine 7. stoljeća, nakon čega slijedi dominacija vegetacije „trave-bukva/hrastovi“ do kraja 13. stoljeća, te naposlijetku vegetacije „trave-grab/hrastovi“ u razdoblju od 14. do početka 20. stoljeća. Obilje spora maha tresetara (Sphagnum) u razdoblju od 11. do kraja 14. stoljeća vjerojatno je utjecano povećanom količinom oborina i učestalijim padalinama tijekom srednjovjekovne klimatske anomalije. Prijelaz iz ombrotrofije u minerotrofiju same cretne površine, tijekom maloga ledenog doba, uzrokovan je promjenom zasićenosti supstrata vodom, s nešto vlažnijim razdobljem do sredine 17. stoljeća i djelomično sušnijim do početka 20. stoljeća. Iako se pelud žitarica ne pojavljuje do kraja 14. stoljeća i udjeli sekundarnih antropogenih indikatora su niski tijekom cijeloga razdoblja srednjeg vijeka, veliki broj pougljenjenih čestica ukazuje na jaču antropogenu aktivnost no što se to može iščitati iz promjenama u biljnome pokrovu. Ipak, snažan porast udjela peluda nedrvenastih vrsta tijekom Seobe naroda više je rezultat procesa sukcesije na površini samoga creta nego nepobitan dokaz avarsko-slavenskoga utjecaja na sastav i strukturu vegetacije. Izravni antropogeni pritisak, koji se očituje učestalom pojavom peluda korovnih vrsta i žitarica, može se pratiti tek od razdoblja kasnoga srednjeg vijeka nadalje., This paper presents the paleoenvironmental reconstruction of a mire sequence near the village Blatuša, with a focus on changes in vegetation composition, hydrological regime and fire history of the Banovina/Kordun area during the last two millennia. For this purpose, pollen, non-pollen and charcoal analysis were done. By the application of CONISS statistical analysis three different pollen assemblage (sub)zones could have been distinguished: a dominance of alder-beech/oaks from the 2nd to the middle of the 7th century, followed by a prevalence of grasses-beech/oaks till the end of the 13th century. Finally, an assemblage of grasses-hornbeam/oaks populated the area from the 14th to the beginning of the 20th century. The high abundance of peat mosses (Sphagnum) from the 11th to the end of the 14th century must indicate increased precipitation and higher frequencies of rainfall during the Medieval Climate Anomaly. Transition from an ombrotrophic to minerotrophic phase of mire evolution during the Little Ice Age is caused by changing in moisture level, with somewhat wetter period prevailing till the middle of the 17th century followed by drier conditions till the beginning of the 20th century. Although cereal pollen grains first appear from the layers dated to the late 14th century and the proportion of secondary anthropogenic indicators were low during the entire Middle Ages, a large number of charcoal particles suggests stronger anthropogenic activity than indicated by observed changes in vegetation composition. Still, a sharp rise of non-arboreal pollen during the Migration period most likely reflect a general natural succession process on mire surface than persuable proof of Avaric-Slavic impact on vegetation. Direct anthropogenic pressure indicated by weeds and cereal pollen can be tracked from the Late Middle Ages onwards.

Am 18. Oktober hat der Bundestag das Gesetz zur Weiterentwicklung des Teilzeitrechts beschlossen, dessen Kernstuck ein Rechtsanspruch auf eine zeitlich begrenzte Teilzeitarbeit (Bruckenteilzeit) ist. Er soll ein Recht auf zeitweise Verringerung der vereinbarten Arbeitszeit und gleichzeitig die Ruckkehr zur vorher vereinbarten Arbeitszeit sichern und gilt in Unternehmen mit mindestens 46 Arbeitnehmern.

Erlauben der gesundheitliche Zustand oder die Umstande jemandem nicht, ein Testament zu verfassen, kommt ein Nottestament in Betracht. Der typische Ort fur die Errichtung eines Nottestaments in der Form eines Dreizeugentestaments ist das Krankenhaus. Der Artikel skizziert die wichtigsten Grundzuge des Erbrechts und erlautert, worauf bei der Errichtung eines Dreizeugentestaments zu achten ist.

In humans, maximum brain development occurs between the third trimester of gestation and 2 years of life. Nutrition during these critical windows of rapid brain development might be essential for later cognitive functioning and behaviour. In the last few years, trends on protein recommendations during infancy and childhood have tended to be lower than that in the past. It remains to be demonstrated that lower protein intakes among healthy infants, a part of being able to reduce obesity risk, is safe in terms of mental performance achievement. Secondary analyses of the EU CHOP, a clinical trial in which infants from five European countries were randomised to be fed a higher or a lower protein content formula during the 1st year of life. Children were assessed at the age of 8 years with a neuropsychological battery of tests that included assessments of memory (visual and verbal), attention (visual, selective, focused and sustained), visual-perceptual integration, processing speed, visual-motor coordination, verbal fluency and comprehension, impulsivity/inhibition, flexibility/shifting, working memory, reasoning, visual-spatial skills and decision making. Internalising, externalising and total behaviour problems were assessed using the Child Behaviour Checklist 4–18. Adjusted analyses considering factors that could influence neurodevelopment, such as parental education level, maternal smoking, child’s gestational age at birth and head circumference, showed no differences between feeding groups in any of the assessed neuropsychological domains and behaviour. In summary, herewith we report on the safety of lower protein content in infant formulae (closer to the content of human milk) according to long-term mental performance.

Background Maternal postpartum depression (PPD) could affect children’s emotional development, increasing later risk of child psychological problems. The aim of our study was to assess the association between child’s emotional and behavioural problems and mother’s PPD, considering maternal current mental health problems (CMP). Methods This is a secondary analysis from the EU-Childhood Obesity Project (NCT00338689). Women completed the Edinburgh Postnatal Depression Scale (EPDS) at, 2, 3 and 6 months after delivery and the General Health Questionnaire (GHQ-12) to assess CMP once the children reached the age of 8 years. EPDS scores > 10 were defined as PPD and GHQ-12 scores > 2 were defined as CMP. The psychological problems of the children at the age of eight were collected by mothers through the Child’s Behaviour Checklist (CBCL). Results 473, 474 and 459 mothers filled in GHQ-12 and CBCL tests at 8 years and EPDS at 2, 3 and 6 months, respectively. Anxiety and depression was significantly increased by maternal EPDS. Children whose mothers had both PPD and CMP exhibited the highest levels of psychological problems, followed by those whose mothers who had only CMP and only PPD. PPD and CMP had a significant effect on child’s total psychological problems (p = 0.033, p

PalDat is the world’s most comprehensive pollen database. At present, the database provides about 22 000 pollen pictures from more than 2500 plant species. Each dataset includes a detailed description of the pollen grain, light- and electron-microscopy images of the pollen grain, images of the plant/inflorescence/flower and relevant literature. Founded in 1997, PalDat had a major revision in 2015. The database contains tools for pollen identification and online publication. Online access to the database and data submission (www.paldat.org) are free of charge.

We examine the relation of soft factors that are derived from the description texts to the probability of successful funding and to the default probability in peer-to-peer lending for two leading European platforms. We find that spelling errors, text length and the mentioning of positive emotion evoking keywords predict the funding probability on the less restrictive of both platforms, which even accepts applications without credit scores. This platform also shows a better risk-return profile. Conditional on being funded, text-related factors hardly predict default probabilities in peer-to-peer lending for both platforms.

Vor allem in der ambulanten Pflege spielt der Einsatz eines Dienstwagens eine Rolle. Bei der Nutzung sind verschiedene Modelle denkbar, je nachdem, wer das Fahrzeug zur Verfugung stellt und ob es nur fur dienstliche oder auch fur private Fahrten uberlassen wird. Der Beitrag erlautert wichtige Rechtsprobleme anhand von Fallbeispielen.

Am 1. April 2017 trat eine grundlegende Reform des Arbeitnehmeruberlassungsgesetzes in Kraft. Die wichtigsten Neuerungen betreffen die maximale Dauer der Uberlassung (18 Monate), Begrenzung der tarifvertraglichen Schlechterstellung der Leiharbeitnehmer gegenuber der Stammbelegschaft im Entleiherbetrieb auf maximal neun Monate sowie ein Verbot des Einsatzes der Leiharbeitnehmer als Streikbrecher.