Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154953/1/feb213721_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154953/2/feb213721.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154953/3/feb213721-sup-0001-FigS1-S3.pd

No Detectable Fertility Benefit from a Single Additional Mating in Wild Stalk-Eyed Flies

Background: Multiple mating by female insects is widespread, and the explanation(s) for repeated mating by females has been the subject of much discussion. Females may profit from mating multiply through direct material benefits that increase their own reproductive output, or indirect genetic benefits that increase offspring fitness. One particular direct benefit that has attracted significant attention is that of fertility assurance, as females often need to mate multiply to achieve high fertility. This hypothesis has never been tested in a wild insect population.Methodology/Principal Findings: Female Malaysian stalk-eyed flies (Teleopsis dalmanni) mate repeatedly during their lifetime, and have been shown to be sperm limited under both laboratory and field conditions. Here we ask whether receiving an additional mating alleviates sperm limitation in wild females. In our experiment one group of females received a single additional mating, while a control group received an interrupted, and therefore unsuccessful, mating. Females that received an additional mating did not lay more fertilised eggs in total, nor did they lay proportionately more fertilised eggs. Female fertility declined significantly through time, demonstrating that females were sperm limited. However, receipt of an additional mating did not significantly alter the rate of this decline.Conclusions/Significance: Our data suggest that the fertility consequences of a single additional mating were small. We discuss this effect (or lack thereof), and suggest that it is likely to be attributed to small ejaculate size, a high proportion of failed copulations, and the presence of X-linked meiotic drive in this species

Medication knowledge, certainty, and risk of errors in health care: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Medication errors are often involved in reported adverse events. Drug therapy, prescribed by physicians, is mostly carried out by nurses, who are expected to master all aspects of medication. Research has revealed the need for improved knowledge in drug dose calculation, and medication knowledge as a whole is poorly investigated. The purpose of this survey was to study registered nurses' medication knowledge, certainty and estimated risk of errors, and to explore factors associated with good results.</p> <p>Methods</p> <p>Nurses from hospitals and primary health care establishments were invited to carry out a multiple-choice test in pharmacology, drug management and drug dose calculations (score range 0-14). Self-estimated certainty in each answer was recorded, graded from 0 = very uncertain to 3 = very certain. Background characteristics and sense of coping were recorded. Risk of error was estimated by combining knowledge and certainty scores. The results are presented as mean (±SD).</p> <p>Results</p> <p>Two-hundred and three registered nurses participated (including 16 males), aged 42.0 (9.3) years with a working experience of 12.4 (9.2) years. Knowledge scores in pharmacology, drug management and drug dose calculations were 10.3 (1.6), 7.5 (1.6), and 11.2 (2.0), respectively, and certainty scores were 1.8 (0.4), 1.9 (0.5), and 2.0 (0.6), respectively. Fifteen percent of the total answers showed a high risk of error, with 25% in drug management. Independent factors associated with high medication knowledge were working in hospitals (p < 0.001), postgraduate specialization (p = 0.01) and completion of courses in drug management (p < 0.01).</p> <p>Conclusions</p> <p>Medication knowledge was found to be unsatisfactory among practicing nurses, with a significant risk for medication errors. The study revealed a need to improve the nurses' basic knowledge, especially when referring to drug management.</p

TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation

<p>Abstract</p> <p>Introduction</p> <p>Signaling downstream of Ras is mediated by three major pathways, Raf/ERK, phosphatidylinositol 3 kinase (PI3K), and Ral guanine nucleotide exchange factor (RalGEF). Ras signal transduction pathways play an important role in breast cancer progression, as evidenced by the frequent over-expression of the Ras-activating epidermal growth factor receptors EGFR and ErbB2. Here we investigated which signal transduction pathways downstream of Ras contribute to EGFR-dependent transformation of telomerase-immortalized mammary epithelial cells HME16C. Furthermore, we examined whether a highly transcriptionally regulated ERK pathway target, PHLDA1 (TDAG51), suggested to be a tumor suppressor in breast cancer and melanoma, might modulate the transformation process.</p> <p>Methods</p> <p>Cellular transformation of human mammary epithelial cells by downstream Ras signal transduction pathways was examined using anchorage-independent growth assays in the presence and absence of EGFR inhibition. TDAG51 protein expression was down-regulated by interfering small hairpin RNA (shRNA), and the effects on cell proliferation and death were examined in Ras pathway-transformed breast epithelial cells.</p> <p>Results</p> <p>Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process. Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts. Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition. Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells.</p> <p>Conclusion</p> <p>Our results suggest that multiple Ras signal transduction pathways contribute to mammary epithelial cell transformation, but that the ERK signaling pathway may be a crucial component downstream of EGFR activation during tumorigenesis. Furthermore, persistent activation of ERK signaling up-regulates TDAG51. This event serves as a negative regulator of both Erk activation as well as matrix-detached cellular proliferation and suggests that TDAG51 opposes ERK-mediated transformation in breast epithelial cells.</p

Inhibition of transforming growth factor α (TGF-α)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868

The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor α (TGF-α)-stimulated growth was completely inhibited by concentrations ≥ 0.3 μM in the PE01 and PE04 cell lines and by ≥ 0.1 μM in SKOV-3 cells. TGF-α inhibition of PE01CDDP growth was reversed by concentrations ≥ 0.1 μM ZM 252868. TGF-α-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations ≥ 0.3 μM, completely inhibited TGF-α-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 μM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor. © 1999 Cancer Research Campaig

Network adaptation improves temporal representation of naturalistic stimuli in drosophila eye: II Mechanisms

Retinal networks must adapt constantly to best present the ever changing visual world to the brain. Here we test the hypothesis that adaptation is a result of different mechanisms at several synaptic connections within the network. In a companion paper (Part I), we showed that adaptation in the photoreceptors (R1-R6) and large monopolar cells (LMC) of the Drosophila eye improves sensitivity to under-represented signals in seconds by enhancing both the amplitude and frequency distribution of LMCs' voltage responses to repeated naturalistic contrast series. In this paper, we show that such adaptation needs both the light-mediated conductance and feedback-mediated synaptic conductance. A faulty feedforward pathway in histamine receptor mutant flies speeds up the LMC output, mimicking extreme light adaptation. A faulty feedback pathway from L2 LMCs to photoreceptors slows down the LMC output, mimicking dark adaptation. These results underline the importance of network adaptation for efficient coding, and as a mechanism for selectively regulating the size and speed of signals in neurons. We suggest that concert action of many different mechanisms and neural connections are responsible for adaptation to visual stimuli. Further, our results demonstrate the need for detailed circuit reconstructions like that of the Drosophila lamina, to understand how networks process information

Astrobiological Complexity with Probabilistic Cellular Automata

Search for extraterrestrial life and intelligence constitutes one of the major endeavors in science, but has yet been quantitatively modeled only rarely and in a cursory and superficial fashion. We argue that probabilistic cellular automata (PCA) represent the best quantitative framework for modeling astrobiological history of the Milky Way and its Galactic Habitable Zone. The relevant astrobiological parameters are to be modeled as the elements of the input probability matrix for the PCA kernel. With the underlying simplicity of the cellular automata constructs, this approach enables a quick analysis of large and ambiguous input parameters' space. We perform a simple clustering analysis of typical astrobiological histories and discuss the relevant boundary conditions of practical importance for planning and guiding actual empirical astrobiological and SETI projects. In addition to showing how the present framework is adaptable to more complex situations and updated observational databases from current and near-future space missions, we demonstrate how numerical results could offer a cautious rationale for continuation of practical SETI searches.Comment: 37 pages, 11 figures, 2 tables; added journal reference belo

Inhibition of CDK4/6 as a novel therapeutic option for neuroblastoma

Background: Neuroblastoma is a neural crest-derived tumor and is the most common cancer in children less than 1 year of age. We hypothesized that aberrations in genes that control the cell cycle could play an important role in the pathogenesis of neuroblastoma and could provide a tractable therapeutic target. Methods: In this study, we screened 131 genes involved in cell cycle regulation at different levels by analyzing the effect of siRNA-mediated gene silencing on the proliferation of neuroblastoma cells. Results: Marked reductions in neuroblastoma cellular proliferation were recorded after knockdown of CCND1 or PLK1. We next showed that pharmacological inhibition of cyclin D1 dependent kinases 4/6 (CDK4/6) with PD 0332991 (palbociclib) reduced the growth of neuroblastoma cell lines, induced G1 cell cycle arrest, and inhibited the cyclin D1-Rb pathway. Conclusion: Selective inhibition of CDK4/6 using palbociclib may provide a new therapeutic option for treating neuroblastoma

Targeting the EGFR in ovarian cancer with the tyrosine kinase inhibitor ZD1839 (“Iressa”).

The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 (‘Iressa’) on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-α stimulated growth was completely inhibited by concentrations of ZD 1839 ⩾0.3 μM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-α stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-α was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-α, EGF and amphiregulin mRNAs were detected by RT–PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(−1) day(−1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit. British Journal of Cancer (2002) 86, 456–462. DOI: 10.1038/sj/bjc/6600058 www.bjcancer.com © 2002 The Cancer Research Campaig

Stable Isotope Composition of Fatty Acids in Organisms of Different Trophic Levels in the Yenisei River

We studied four-link food chain, periphytic microalgae and water moss (producers), trichopteran larvae (consumers I), gammarids (omnivorous – consumers II) and Siberian grayling (consumers III) at a littoral site of the Yenisei River on the basis of three years monthly sampling. Analysis of bulk carbon stable isotopes and compound specific isotope analysis of fatty acids (FA) were done. As found, there was a gradual depletion in 13C contents of fatty acids, including essential FA upward the food chain. In all the trophic levels a parabolic dependence of δ13C values of fatty acids on their degree of unsaturation/chain length occurred, with 18:2n-6 and 18:3n-3 in its lowest point. The pattern in the δ13C differences between individual fatty acids was quite similar to that reported in literature for marine pelagic food webs. Hypotheses on isotope fractionation were suggested to explain the findings