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Sample records for cdk4 regulates recruitment

  1. Cell Cycle Regulating Kinase Cdk4 as a Potential Target for Tumor Cell Treatment and Tumor Imaging

    Directory of Open Access Journals (Sweden)

    Franziska Graf

    2009-01-01

    Full Text Available The cyclin-dependent kinase (Cdk-cyclin D/retinoblastoma (pRb/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two I124-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-yl-phenylamino-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl-pyridin-2-yl-amino-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB. Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [I124]CKIA and [I124]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies.

  2. Purification, characterization, and kinetic mechanism of cyclin D1. CDK4, a major target for cell cycle regulation.

    Science.gov (United States)

    Konstantinidis, A K; Radhakrishnan, R; Gu, F; Rao, R N; Yeh, W K

    1998-10-09

    The cyclin D1.CDK4-pRb (retinoblastoma protein) pathway plays a central role in the cell cycle, and its deregulation is correlated with many types of cancers. As a major drug target, we purified dimeric cyclin D1.CDK4 complex to near-homogeneity by a four-step procedure from a recombinant baculovirus-infected insect culture. We optimized the kinase activity and stability and developed a reproducible assay. We examined several catalytic and kinetic properties of the complex and, via steady-state kinetics, derived a kinetic mechanism with a peptide (RbING) and subsequently investigated the mechanistic implications with a physiologically relevant protein (Rb21) as the phosphoacceptor. The complex bound ATP 130-fold tighter when Rb21 instead of RbING was used as the phosphoacceptor. By using staurosporine and ADP as inhibitors, the kinetic mechanism of the complex appeared to be a "single displacement or Bi-Bi" with Mg2+.ATP as the leading substrate and phosphorylated RbING as the last product released. In addition, we purified a cyclin D1-CDK4 fusion protein to homogeneity by a three-step protocol from another recombinant baculovirus culture and observed similar kinetic properties and mechanisms as those from the complex. We attempted to model staurosporine in the ATP-binding site of CDK4 according to our kinetic data. Our biochemical and modeling data provide validation of both the complex and fusion protein as highly active kinases and their usefulness in antiproliferative inhibitor discovery.

  3. Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress.

    Science.gov (United States)

    Icreverzi, Amalia; de la Cruz, Aida Flor A; Walker, David W; Edgar, Bruce A

    2015-10-01

    Mitochondrial dysfunction has been implicated in human diseases, including cancer, and proposed to accelerate aging. The Drosophila Cyclin-dependent protein kinase complex cyclin D/cyclin-dependent kinase 4 (CycD/Cdk4) promotes cellular growth by stimulating mitochondrial biogenesis. Here, we examine the neurodegenerative and aging consequences of altering CycD/Cdk4 function in Drosophila. We show that pan-neuronal loss or gain of CycD/Cdk4 increases mitochondrial superoxide, oxidative stress markers, and neurodegeneration and decreases lifespan. We find that RNAi-mediated depletion of the mitochondrial transcription factor, Tfam, can abrogate CycD/Cdk4's detrimental effects on both lifespan and neurodegeneration. This indicates that CycD/Cdk4's pathological consequences are mediated through altered mitochondrial function and a concomitant increase in reactive oxygen species. In support of this, we demonstrate that CycD/Cdk4 activity levels in the brain affect the expression of a set of 'oxidative stress' genes. Our results indicate that the precise regulation of neuronal CycD/Cdk4 activity is important to limit mitochondrial reactive oxygen species production and prevent neurodegeneration. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. A novel role for the cell cycle regulatory complex cyclin D1?CDK4 in gluconeogenesis

    OpenAIRE

    Hosooka, Tetsuya; Ogawa, Wataru

    2015-01-01

    Dysregulation of gluconeogenesis is a key pathological feature of type 2 diabetes. However, the molecular mechanisms underlying the regulation of gluconeogenesis remain unclear. Bhalla et?al. recently reported that cyclin D1 suppresses hepatic gluconeogenesis through CDK4?dependent phosphorylation of PGC1alpha and consequent inhibition of its activity. The cyclin D1?CDK4 might thus serve as an important link between the cell cycle and control of energy metabolism through modulation of PGC1alp...

  5. A novel role for the cell cycle regulatory complex cyclin D1-CDK4 in gluconeogenesis.

    Science.gov (United States)

    Hosooka, Tetsuya; Ogawa, Wataru

    2016-01-01

    Dysregulation of gluconeogenesis is a key pathological feature of type 2 diabetes. However, the molecular mechanisms underlying the regulation of gluconeogenesis remain unclear. Bhalla et al. recently reported that cyclin D1 suppresses hepatic gluconeogenesis through CDK4-dependent phosphorylation of PGC1alpha and consequent inhibition of its activity. The cyclin D1-CDK4 might thus serve as an important link between the cell cycle and control of energy metabolism through modulation of PGC1alpha activity.

  6. DACH1 regulates cell cycle progression of myeloid cells through the control of cyclin D, Cdk 4/6 and p21{sup Cip1}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae-Woong; Kim, Hyeng-Soo; Kim, Seonggon; Hwang, Junmo; Kim, Young Hun; Lim, Ga Young [School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Sohn, Wern-Joo [Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu 700-412 (Korea, Republic of); Yoon, Suk-Ran [Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806 (Korea, Republic of); Kim, Jae-Young [Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu 700-412 (Korea, Republic of); Park, Tae Sung [Department of Laboratory Medicine, Kyung Hee University School of Medicine, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702 (Korea, Republic of); Park, Kwon Moo [Department of Anatomy, Kyungpook National University School of Medicine, Daegu 700-422 (Korea, Republic of); Ryoo, Zae Young [School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Lee, Sanggyu, E-mail: slee@knu.ac.kr [School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701 (Korea, Republic of)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer DACH1 increases cyclin D, F and Cdk 1, 4, 6 in mouse myeloid progenitor cells. Black-Right-Pointing-Pointer The knockdown of DACH1 blocked the cell cycle progression of HL-60 cells. Black-Right-Pointing-Pointer The novel effect of DACH1 related with cell cycle regulation and leukemogenesis. -- Abstract: The cell-fate determination factor Dachshund, a component of the Retinal Determination Gene Network (RDGN), has a role in breast tumor proliferation through the repression of cyclin D1 and several key regulators of embryonic stem cell function, such as Nanog and Sox2. However, little is known about the role of DACH1 in a myeloid lineage as a cell cycle regulator. Here, we identified the differential expression levels of extensive cell cycle regulators controlled by DACH1 in myeloid progenitor cells. The forced expression of DACH1 induced p27{sup Kip1} and repressed p21{sup Cip1}, which is a pivotal characteristic of the myeloid progenitor. Furthermore, DACH1 significantly increased the expression of cyclin D1, D3, F, and Cdk 1, 4, and 6 in myeloid progenitor cells. The knockdown of DACH1 blocked the cell cycle progression of HL-60 promyeloblastic cells through the decrease of cyclin D1, D3, F, and Cdk 1, 4, and 6 and increase in p21{sup Cip1}, which in turn decreased the phosphorylation of the Rb protein. The expression of Sox2, Oct4, and Klf4 was significantly up-regulated by the forced expression of DACH1 in mouse myeloid progenitor cells.

  7. The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPalpha is dispensable for C/EBPalpha-mediated growth regulation in vivo

    DEFF Research Database (Denmark)

    Porse, Bo Torben; Pedersen, Thomas Askov; Hasemann, Marie Sigurd

    2006-01-01

    The C/EBPalpha transcription factor regulates growth and differentiation of several tissues during embryonic development. Several hypotheses as to how C/EBPalpha inhibits cellular growth in vivo have been derived, mainly from studies of tissue culture cells. In fetal liver it has been proposed......, carrying a modified cebpa allele lacking amino acids 180 to 194, were born at the Mendelian ratio, reached adulthood, and displayed no apparent adverse phenotypes. When fetal livers from the DeltaPHR mice were analyzed for their expression of cell cycle markers, bromodeoxyuridine incorporation, cyclin...... is dispensable for proper embryonic development of, and cell cycle control in, the liver. Surprisingly, control experiments performed in C/EBPalpha null fetal livers yielded similar results....

  8. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.

    Science.gov (United States)

    Puntervoll, Hanne Eknes; Yang, Xiaohong R; Vetti, Hildegunn Høberg; Bachmann, Ingeborg M; Avril, Marie Françoise; Benfodda, Meriem; Catricalà, Caterina; Dalle, Stéphane; Duval-Modeste, Anne B; Ghiorzo, Paola; Grammatico, Paola; Harland, Mark; Hayward, Nicholas K; Hu, Hui-Han; Jouary, Thomas; Martin-Denavit, Tanguy; Ozola, Aija; Palmer, Jane M; Pastorino, Lorenza; Pjanova, Dace; Soufir, Nadem; Steine, Solrun J; Stratigos, Alexander J; Thomas, Luc; Tinat, Julie; Tsao, Hensin; Veinalde, Ruta; Tucker, Margaret A; Bressac-de Paillerets, Brigitte; Newton-Bishop, Julia A; Goldstein, Alisa M; Akslen, Lars A; Molven, Anders

    2013-04-01

    CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (pMC1R red hair colour variants compared with subjects with one tumour (p=0.010). Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.

  9. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.

    Science.gov (United States)

    Deng, Jiehui; Wang, Eric S; Jenkins, Russell W; Li, Shuai; Dries, Ruben; Yates, Kathleen; Chhabra, Sandeep; Huang, Wei; Liu, Hongye; Aref, Amir R; Ivanova, Elena; Paweletz, Cloud P; Bowden, Michaela; Zhou, Chensheng W; Herter-Sprie, Grit S; Sorrentino, Jessica A; Bisi, John E; Lizotte, Patrick H; Merlino, Ashley A; Quinn, Max M; Bufe, Lauren E; Yang, Annan; Zhang, Yanxi; Zhang, Hua; Gao, Peng; Chen, Ting; Cavanaugh, Megan E; Rode, Amanda J; Haines, Eric; Roberts, Patrick J; Strum, Jay C; Richards, William G; Lorch, Jochen H; Parangi, Sareh; Gunda, Viswanath; Boland, Genevieve M; Bueno, Raphael; Palakurthi, Sangeetha; Freeman, Gordon J; Ritz, Jerome; Haining, W Nicholas; Sharpless, Norman E; Arthanari, Haribabu; Shapiro, Geoffrey I; Barbie, David A; Gray, Nathanael S; Wong, Kwok-Kin

    2018-02-01

    Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo , due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Jenkins et al., p. 196 This article is highlighted in the In This Issue feature, p. 127 . ©2017 American Association for Cancer Research.

  10. Co-expression of CDC2 and CDK4 in human cancer cells is disrupted following γ-irradiation

    International Nuclear Information System (INIS)

    Warenius, Hilmar; Seabra, Laurence

    1995-01-01

    maintained their cdc2/cdk4 relationship. There was some progressive recovery of the cdc2/cdk4 relationship over this time course. Following irradiation the levels of both cdk4 and cdc4 proteins were altered. Conclusions: The close correlation, reported here, between cdc2 and cdk4 expression in 20 human in vitro cell lines which is markedly disrupted in 7 of these following 2Gy of γ-irradiation, suggests the possible existence of a radiation-sensitive mechanism involving co-regulation of expression of cdc2 and cdk4

  11. Recent advances of highly selective CDK4/6 inhibitors in breast cancer

    Directory of Open Access Journals (Sweden)

    Hanxiao Xu

    2017-04-01

    Full Text Available Abstract Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6, which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991, ribociclib (LEE011, and abemaciclib (LY2835219. Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.

  12. Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy.

    Science.gov (United States)

    Kong, Yan; Sheng, Xinan; Wu, Xiaowen; Yan, Junya; Ma, Meng; Yu, Jiayi; Si, Lu; Chi, Zhihong; Cui, Chuanliang; Dai, Jie; Li, Yiqian; Yu, Huan; Xu, Tianxiao; Tang, Huan; Tang, Bixia; Mao, Lili; Lian, Bin; Wang, Xuan; Yan, Xieqiao; Li, Siming; Guo, Jun

    2017-11-15

    Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma. Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1 , and P16 INK4a , by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16 INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1 , and P16 INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16 INK4a loss was significantly shorter than that for patients without such aberrations ( P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16 INK4a loss, and Ccnd1 gain plus P16 INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946-57. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jingling Jin

    2016-07-01

    Full Text Available The development of non-alcoholic fatty liver disease (NAFLD is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC. The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD.

  14. CDK4 amplification predicts recurrence of well-differentiated liposarcoma of the abdomen.

    Directory of Open Access Journals (Sweden)

    Sanghoon Lee

    Full Text Available The absence of CDK4 amplification in liposarcomas is associated with favorable prognosis. We aimed to identify the factors associated with tumor recurrence in patients with well-differentiated (WD and dedifferentiated (DD liposarcomas.From 2000 to 2010, surgical resections for 101 WD and DD liposarcomas were performed. Cases in which complete surgical resections with curative intent were carried out were selected. MDM2 and CDK4 gene amplification were analyzed by quantitative real-time polymerase chain reaction (Q-PCR.There were 31 WD and 17 DD liposarcomas. Locoregional recurrence was observed in 11 WD and 3 DD liposarcomas. WD liposarcomas showed better patient survival compared to DD liposarcomas (P<0.05. Q-PCR analysis of the liposarcomas revealed the presence of CDK4 amplification in 44 cases (91.7% and MDM2 amplification in 46 cases (95.8%. WD liposarcomas with recurrence after surgical resection had significantly higher levels of CDK4 amplification compared to those without recurrence (P = 0.041. High level of CDK4 amplification (cases with CDK4 amplification higher than the median 7.54 was associated with poor recurrence-free survival compared to low CDK4 amplification in both univariate (P = 0.012 and multivariate analyses (P = 0.020.Level of CDK4 amplification determined by Q-PCR was associated with the recurrence of WD liposarcomas after surgical resection.

  15. Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc−/+ mice

    International Nuclear Information System (INIS)

    Karim, Baktiar O; Rhee, Ki-Jong; Liu, Guosheng; Zheng, Dongfeng; Huso, David L

    2013-01-01

    Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Colorectal cancers have a prolonged latency following initiation that may span decades providing ample time for implementing a chemoprevention strategy that could block or reverse the progression to CRC. Cdk4 pathway alterations have been linked to a number of cancers including CRC. In these experiments we focused on the Cdk4 pathway and its role in intestinal tumorigenesis as a possible target in chemoprevention strategies. We evaluated the effect of Cdk4 blockade on the prevention of intestinal tumor formation by crossing Cdk4 −/− mice to Apc −/+ mice. In addition, we tested the effect of the dietary compound silibinin on the Cdk4 pathway in Apc −/+ mice and HT-29 colon cancer cells in culture. Cdk4 −/− mice backcrossed to Apc −/+ mice reduced intestinal adenoma formation compared to Apc −/+ controls. Silibinin effectively targeted the Cdk4 pathway causing hypophosphorylation of the retinoblastoma protein, inhibited cell growth, and induced apoptosis. As a result silibinin blocked the development of intestinal adenomas by 52% in this genetic model (Apc −/+ mice) of early events in colorectal cancer formation. No toxic abnormalities were detected in mice which received silibinin. Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas

  16. Diverse models for the prediction of CDK4 inhibitory activity of ...

    Indian Academy of Sciences (India)

    which form in a cyclical fashion.2 The CDKs are a family of heterodimeric Ser/Thr protein kinases each ... to proliferation. The major Cdk4/cyclin D substrate is the product of the retinoblastoma gene (pRB).8 Dur- ... whose products are required for S phase.9,10 Alter- ations in the cascade involving CDK4, CDK6, cyclin D,.

  17. Azolium analogues as CDK4 inhibitors: Pharmacophore modeling, 3D QSAR study and new lead drug discovery

    Science.gov (United States)

    Rondla, Rohini; Padma Rao, Lavanya Souda; Ramatenki, Vishwanath; Vadija, Rajender; Mukkera, Thirupathi; Potlapally, Sarita Rajender; Vuruputuri, Uma

    2017-04-01

    The cyclin-dependent kinase 4 (CDK4) enzyme is a key regulator in cell cycle G1 phase progression. It is often overexpressed in variety of cancer cells, which makes it an attractive therapeutic target for cancer treatment. A number of chemical scaffolds have been reported as CDK4 inhibitors in the literature, and in particular azolium scaffolds as potential inhibitors. Here, a ligand based pharmacophore modeling and an atom based 3D-QSAR analyses for a series of azolium based CDK4 inhibitors are presented. A five point pharmacophore hypothesis, i.e. APRRR with one H-bond acceptor (A), one positive cationic feature (P) and three ring aromatic sites (R) is developed, which yielded an atom based 3D-QSAR model that shows an excellent correlation coefficient value- R2 = 0.93, fisher ratio- F = 207, along with good predictive ability- Q2 = 0.79, and Pearson R value = 0.89. The visual inspection of the 3D-QSAR model, with the most active and the least active ligands, demonstrates the favorable and unfavorable structural regions for the activity towards CDK4. The roles of positively charged nitrogen, the steric effect, ligand flexibility, and the substituents on the activity are in good agreement with the previously reported experimental results. The generated 3D QSAR model is further applied as query for a 3D database screening, which identifies 23 lead drug candidates with good predicted activities and diverse scaffolds. The ADME analysis reveals that, the pharmacokinetic parameters of all the identified new leads are within the acceptable range.

  18. Deletion of the p107/p130-binding domain of Mip130/LIN-9 bypasses the requirement for CDK4 activity for the dissociation of Mip130/LIN-9 from p107/p130-E2F4 complex.

    Science.gov (United States)

    Sandoval, Raudel; Pilkinton, Mark; Colamonici, Oscar R

    2009-10-15

    Mip130/LIN-9 is part of a large complex that includes homologs of the Drosophila dREAM (drosophila RB-like, E2F, and Myb) and C. elegans DRM complexes. This complex also includes proteins such as Mip40/LIN-37, Mip120/LIN-54, and LIN-52. In mammalian cells, Mip130/LIN-9 specifically associates with the p107/p130-E2F4 repressor complex in G0/G1 and with B-Myb in S-phase. However, little is known about how the transition occurs and whether Mip130/LIN-9 contributes to the repressor effect of p107/p130. In this report, we demonstrate that Mip130/LIN-9, Mip40/LIN-37, Mip120/LIN-54, and Sin3b form a core complex, the Mip Core Complex or LIN Complex (MCC/LINC), which is detectable in all phases of the cell cycle. This complex specifically recruits transcriptional repressors such as p107, p130, E2F4 and HDAC1 in G0/G1, and B-Myb in S-phase. Importantly, we provide strong evidence that the transition between repressors and activators of transcription is mediated by CDK4, through the phosphorylation of the pocket proteins, p107 and p130. The requirement for CDK4 activity is bypassed by the deletion of the first 84 amino acids (Mip130/LIN-9(Delta84)), since this mutant is unable to interact with p107/p130 in G0/G1, while maintaining its association with B-Myb. Importantly, the Mip130/LIN-9(Delta84) allele rescues the low expression of G1/S genes observed in CDK4(-/-) MEFs demonstrating that Mip130/LIN-9 contributes to the repression of these E2F-regulated genes in G0/G1.

  19. Expression of cdk4 and p16 in Oral Lichen Planus.

    Science.gov (United States)

    Goel, Sinny; Khurana, Nita; Marwah, Akanksha; Gupta, Sunita

    2015-01-01

    The purpose of this study was to evaluate the expression of cdk4 and p16, the proteins implicated in hyperproliferation and arrest in oral lichen planus and to compare their expression in erosive and non-erosive oral lichen planus and with normal mucosa and oral squamous cell carcinoma. Analysis of cdk4 and p16 expression was done in 43 erosive oral lichen planus (EOLP) and 17 non-erosive oral lichen planus (NOLP) cases, 10 normal mucosa and 10 oral squamous cell carcinoma (OSCC) cases with immunohistochemistry. This study demonstrated a significantly increased expression of cytoplasmic cdk4 (80% cases, cells stained - 19.6%), and cytoplasmic p16 (68.3% cases, cells stained - 16.4%) in oral lichen planus (OLP) compared to normal mucosa. cdk4 was much higher in OSCC in both cytoplasm and nuclei compared to normal mucosa. Also, while comparing OLP with positive control, significant difference was noted for cdk4 and p16, with expression being more in OSCC. While comparing EOLP with NOLP; significant differences were seen for cdk4 cytoplasmic staining only, for number of cases with positive staining as well as number of cells stained. Overexpression of cytoplasmic cdk4 and p16 was registered in oral lichen planus, however considerably lower than in squamous cell carcinoma. Erosive oral lichen planus demonstrated overexpression of cytoplasmic cdk4 and premalignant nature compared to non-erosive lesion. Therefore there is an obvious possibility for cytoplasmic expression of cdk4 and p16 to predict malignant potential of oral lichen planus lesions.

  20. Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Jin, Jingling; Valanejad, Leila; Nguyen, Thuy Phuong; Lewis, Kyle; Wright, Mary; Cast, Ashley; Stock, Lauren; Timchenko, Lubov; Timchenko, Nikolai A

    2016-07-19

    The development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD)-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Inactivation of TGF-β signaling in lung cancer results in increased CDK4 activity that can be rescued by ELF

    International Nuclear Information System (INIS)

    Baek, Hye Jung; Kim, Sang Soo; Silva, Fabio May da; Volpe, Eugene A.; Evans, Stephen; Mishra, Bibhuti; Mishra, Lopa; Blair Marshall, M.

    2006-01-01

    Escape from TGF-β inhibition of proliferation is a hallmark of multiple cancers including lung cancer. We explored the role of ELF, crucial TGF-β adaptor protein identified from endodermal progenitor cells, in lung carcinogenesis and cell-cycle regulation. Interestingly, elf -/- mice develop multiple defects that include lung, liver, and cardiac abnormalities. Four out of 6 lung cancer and mesothelioma cell lines displayed deficiency of ELF expression with increased CDK4 expression. Immunohistochemistry and Western blot analysis of primary human lung cancers also showed decreased ELF expression and overexpression of CDK4. Moreover, rescue of ELF in ELF-deficient cell lines decreased the expression of CDK4 and resulted in accumulation of G1/S checkpoint arrested cells. These results suggest that disruption in TGF-β signaling mediated by loss of ELF in lung cancer leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-β adaptor protein in suppressing early lung cancer

  2. Simulation of Different Truncated p16INK4a Forms and In Silico Study of Interaction with Cdk4

    Directory of Open Access Journals (Sweden)

    Najmeh Fahham

    2009-01-01

    Full Text Available Protein-protein interactions studies can greatly increase the amount of structural and functional information pertaining to biologically active molecules and processes. The information obtained from such studies can lead to design and application of new modification in order to obtain a desired bioactivity. Many application packages and servers performing docking, such as HEX, DOT, AUTODOCK, and ZDOCK are now available for predicting the lowest free energy state of a protein complex. In this study, we have focused on cyclin-dependent kinase 4 (Cdk4, a key molecule in the regulation of cell cycle progression at the G1-S phase restriction point and p16INK4a, a tumor suppressor which inhibits Cdk4 activity. Truncated structures were created to find the more critical regions of p16 for interaction. The tertiary structures were determined by ProSAL, GENO3D Web Server. We evaluated their interactions with Cdk4 using two docking systems, HEX 4.5 and DOT 1. Calculations were performed on a high-speed computer. Minimizations and visualizations were carried out by PdbViewer 3.7. Considering shape and shape/electrostatic total energy, structures containing ANK II, III and IV motifs that lack the N-terminal region of the full length p16 molecule showed the best fi t complexes among the p16 truncated forms. The free energies were compatible with that of p16 full length original form, the full length. It seems that the N-terminal of the molecule is not crucial for the interaction since the truncated structure containing only this region did not show a good total energy.

  3. Immunohistochemical analysis of the D-type cyclin-dependent kinases Cdk4 and Cdk6, using a series of monoclonal antibodies.

    Science.gov (United States)

    Lukas, C; Jensen, S K; Bartkova, J; Lukas, J; Bartek, J

    1999-06-01

    Cellular signal transduction cascades triggered by mitogenic or antiproliferative cues eventually converge on a biochemical mechanism centered around the retinoblastoma tumor suppressor (pRb), the so-called RB pathway that governs G1-phase progression and guards the commitment to enter S phase. pRb, together with its immediate upstream regulators, the D-type cyclins, their partner cyclin-dependent kinases Cdk4 and Cdk6, and the Cdk inhibitors, form a functional unit that is involved in major decisions about cellular fate, and whose components, including the proto-oncogenic cyclin D-dependent kinases, are commonly deregulated in many types of cancer. We report here the production and characterization of a series of 12 monoclonal antibodies (MAbs) that specifically recognize either Cdk4 or Cdk6. These antibodies are proving to be invaluable molecular probes for defining abundance, subcellular localization, binding partners, and ultimately the function(s) of these cell cycle-regulatory kinases. Localization of the target epitopes was mapped by peptide enzyme-linked immunoadsorbent assay (ELISA), and two antibodies recognizing sequences adjacent to N-terminus of Cdk4 can discriminate between the wild-type protein and the oncogenic, melanoma-associated R24C mutant of this kinase. Individual antibodies of our panel recognize distinct pools of Cdk4/6, a feature reflected by their differential applicability in immunoblotting, immunoprecipitation, kinase assays, and immunostaining including immunohistochemistry on archival paraffin-embedded tissue sections. Collectively, the antibodies described in this study provide the means for immunochemical analyses of the cyclin D-dependent kinases in human and animal cells, and represent useful molecular tools that should help better understand the biological roles of Cdk4 and Cdk6 in normal cell-cycle control, and their oncogenic activity in tumor cells.

  4. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Lee, Janet [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Lee, Chang-Woo [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Suwon, Gyeonggi 440-746 (Korea, Republic of); Yang, Kwangmo [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-709 (Korea, Republic of); Lee, Chang Geun, E-mail: cglee@dirams.re.kr [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of)

    2013-01-25

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

  5. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    International Nuclear Information System (INIS)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

    2013-01-01

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24 − /CD44 + ) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer

  6. Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells

    NARCIS (Netherlands)

    The, Inge; Ruijtenberg, Suzan; Bouchet, Benjamin P; Cristobal, Alba; Prinsen, Martine B W; van Mourik, Tim; Koreth, John; Xu, Huihong; Heck, Albert J R; Akhmanova, Anna; Cuppen, Edwin; Boxem, Mike; Muñoz, Javier; van den Heuvel, Sander

    2015-01-01

    Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases,

  7. CCND1-CDK4-mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo.

    Science.gov (United States)

    Mende, Nicole; Kuchen, Erika E; Lesche, Mathias; Grinenko, Tatyana; Kokkaliaris, Konstantinos D; Hanenberg, Helmut; Lindemann, Dirk; Dahl, Andreas; Platz, Alexander; Höfer, Thomas; Calegari, Federico; Waskow, Claudia

    2015-07-27

    Maintenance of stem cell properties is associated with reduced proliferation. However, in mouse hematopoietic stem cells (HSCs), loss of quiescence results in a wide range of phenotypes, ranging from functional failure to extensive self-renewal. It remains unknown whether the function of human HSCs is controlled by the kinetics of cell cycle progression. Using human HSCs and human progenitor cells (HSPCs), we report here that elevated levels of CCND1-CDK4 complexes promoted the transit from G0 to G1 and shortened the G1 cell cycle phase, resulting in protection from differentiation-inducing signals in vitro and increasing human leukocyte engraftment in vivo. Further, CCND1-CDK4 overexpression conferred a competitive advantage without impacting HSPC numbers. In contrast, accelerated cell cycle progression mediated by elevated levels of CCNE1-CDK2 led to the loss of functional HSPCs in vivo. Collectively, these data suggest that the transition kinetics through the early cell cycle phases are key regulators of human HSPC function and important for lifelong hematopoiesis. © 2015 Mende et al.

  8. Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System

    Directory of Open Access Journals (Sweden)

    Stephen T. Hallett

    2017-10-01

    Full Text Available Summary: Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions. : Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations. Keywords: Cdc37, CDK, chaperone, CIP/KIP, cyclin D, Hsp90, INK, kinase, palbociclib, ribociclib

  9. 1α,25 dihydroxi-vitamin D{sub 3} modulates CDK4 and CDK6 expression and localization

    Energy Technology Data Exchange (ETDEWEB)

    Irazoqui, Ana P.; Heim, Nadia B.; Boland, Ricardo L.; Buitrago, Claudia G., E-mail: cbuitrag@criba.edu.ar

    2015-03-27

    We recently reported that the vitamin D receptor (VDR) and p38 MAPK participate in pro-differentiation events triggered by 1α,25(OH){sub 2}-vitamin D{sub 3} [1,25D] in skeletal muscle cells. Specifically, our studies demonstrated that 1,25D promotes G0/G1 arrest of cells inducing cyclin D3 and cyclin dependent kinases inhibitors (CKIs) p21{sup Waf1/Cip1} and p27{sup Kip1} expression in a VDR and p38 MAPK dependent manner. In this work we present data indicating that cyclin-dependent kinases (CDKs) 4 and 6 also play a role in the mechanism by which 1,25D stimulates myogenesis. To investigate VDR involvement in hormone regulation of CDKs 4 and 6, we significantly reduced its expression by the use of a shRNA against mouse VDR, generating the skeletal muscle cell line C2C12-VDR. Investigation of changes in cellular cycle regulating proteins by immunoblotting showed that the VDR is involved in the 1,25D –induced CDKs 4 and 6 protein levels at 6 h of hormone treatment. CDK4 levels remains high during S phase peak and G0/G1 arrest while CDK6 expression decreases at 12 h and increases again al 24 h. The up-regulation of CDKs 4 and 6 by 1,25D (6 h) was abolished in C2C12 cells pre-treated with the ERK1/2 inhibitor, UO126. Moreover, CDKs 4 and 6 expression induced by the hormone nor was detected when α and β isoforms of p38 MAPK were inhibited by compound SB203580. Confocal images show that there is not co-localization between VDR and CDKs at 6 h of hormone treatment, however CDK4 and VDR co-localizates in nucleus after 12 h of 1,25D exposure. Of relevance, at this time 1,25D promotes CDK6 localization in a peri-nuclear ring. Our data demonstrate that the VDR, ERK1/2 and p38 MAPK are involved in the control of CDKs 4 and 6 by 1,25D in skeletal muscle cells sustaining the operation of a VDR and MAPKs –dependent mechanism in hormone modulation of myogenesis. - Highlights: • 1,25D modulates CDKs 4 and 6 expression in skeletal muscle cells. • CDK4 co

  10. CDK4/6 blockade in breast cancer: current experience and future perspectives.

    Science.gov (United States)

    Zardavas, Dimitrios; Pondé, Noam; Tryfonidis, Konstantinos

    2017-12-01

    Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer. Areas covered: This review illustrates how CDK4/6-selective inhibitors got approval for the treatment of patients with either newly diagnosed or pretreated advanced hormone receptor positive, HER2-negative breast cancer. Furthermore, data about potential predictive biomarkers, as well as preclinical and preliminary clinical evidence for potential antitumor activity of CDK4/6 inhibition in other breast cancer subtypes is provided. Expert opinion: Future clinical development of CDK4/6 inhibitors in breast cancer will focus on the following aspects: i) optimization of treatment sequencing for patients with advanced disease, ii) early-stage disease, iii) other subtypes of breast cancer in rationally chosen therapeutic combinations and iv) the identification of predictive biomarkers.

  11. Diverse models for the prediction of CDK4 inhibitory activity of ...

    Indian Academy of Sciences (India)

    Decision tree, random forest, moving average analysis (MAA), multiple linear regression (MLR), partial least square regression (PLSR) and principal component regression (PCR) were used to develop models for prediction of CDK4 inhibitory activity. The statistical significance of models was assessed through specificity, ...

  12. GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium.

    Science.gov (United States)

    Rojas, Anabel; Kong, Sek Won; Agarwal, Pooja; Gilliss, Brian; Pu, William T; Black, Brian L

    2008-09-01

    The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.

  13. Comparative proteome profiling of MCF10A and 184A1 human breast epithelial cells emphasized involvement of CDK4 and cyclin D3 in cell proliferation.

    Science.gov (United States)

    Bhaskaran, Nimesh; Lin, Kah Wai; Gautier, Aude; Woksepp, Hanna; Hellman, Ulf; Souchelnytskyi, Serhiy

    2009-01-01

    Acquiring high proliferation rate is crucial for carcinogenic transformation of cells. We report here proteome profiling of human breast epithelial cells with low (184A1) and high (MCF10A) proliferation rates. We identified 183 proteins in 184A1 and 318 proteins in MCF10A cells. These datasets provide the most comprehensive proteome annotations of 184A1 and MCF10A cells. Proteins were taken for identification from 2-D gels in a systematic and unbiased way. Functional clustering of the identified proteins showed similarities in distribution of proteins to the same functional domains, indicating similarities in proteomes of 184A1 and MCF10A cells. Among observed differences in protein expression, we validated correlation of expression of endogenous cyclin-dependent kinase 4 (CDK4), cyclin D3, cdc25B, and p38γ with cell proliferation. Furthermore, down-regulation of CDK4 and cyclin D3 with specific siRNA inhibited cell proliferation, which emphasized the role of CDK4 and cyclin D3 in enhancement of cell proliferation rate of human breast epithelial cells. Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies.

    Directory of Open Access Journals (Sweden)

    Nagasundaram N

    Full Text Available The cyclin-dependent kinase 4 (CDK4-cyclin D1 complex plays a crucial role in the transition from the G1 phase to S phase of the cell cycle. Among the CDKs, CDK4 is one of the genes most frequently affected by somatic genetic variations that are associated with various forms of cancer. Thus, because the abnormal function of the CDK4-cyclin D1 protein complex might play a vital role in causing cancer, CDK4 can be considered a genetically validated therapeutic target. In this study, we used a systematic, integrated computational approach to identify deleterious nsSNPs and predict their effects on protein-protein (CDK4-cyclin D1 and protein-ligand (CDK4-flavopiridol interactions. This analysis resulted in the identification of possible inhibitors of mutant CDK4 proteins that bind the conformations induced by deleterious nsSNPs. Using computational prediction methods, we identified five nsSNPs as highly deleterious: R24C, Y180H, A205T, R210P, and R246C. From molecular docking and molecular dynamic studies, we observed that these deleterious nsSNPs affected CDK4-cyclin D1 and CDK4-flavopiridol interactions. Furthermore, in a virtual screening approach, the drug 5_7_DIHYDROXY_ 2_ (3_4_5_TRI HYDROXYPHENYL _4H_CHROMEN_ 4_ONE displayed good binding affinity for proteins with the mutations R24C or R246C, the drug diosmin displayed good binding affinity for the protein with the mutation Y180H, and the drug rutin displayed good binding affinity for proteins with the mutations A205T and R210P. Overall, this computational investigation of the CDK4 gene highlights the link between genetic variation and biological phenomena in human cancer and aids in the discovery of molecularly targeted therapies for personalized treatment.

  15. Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification.

    Science.gov (United States)

    Lyle, Pamela L; Bridge, Julia A; Simpson, Jean F; Cates, Justin M; Sanders, Melinda E

    2016-06-01

    Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification. We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26-84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4. This study examined molecular changes in the well-differentiated liposarcomatous components of MPT. Despite histological similarity to well-differentiated liposarcoma of soft tissues, liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma. © 2015 John Wiley & Sons Ltd.

  16. Crystal structure of the homolog of the oncoprotein gankyrin, an interactor of Rb and CDK4/6.

    Science.gov (United States)

    Padmanabhan, Balasundaram; Adachi, Naruhiko; Kataoka, Kazuhiro; Horikoshi, Masami

    2004-01-09

    The oncoprotein gankyrin plays a central role in tumorigenesis and cell proliferation. Gankyrin interacts with the retinoblastoma tumor suppressor (Rb) and cyclin-dependent kinase 4/6 (CDK4/6), increases phosphorylation at specific residues of Rb by CDK4/6 in vivo, and promotes tumorigenesis. The phosphorylation of Rb by CDK4/6 leads to the deregulation of the cell cycle during G1/S transition. Although how phosphorylation occurs on Rb has been studied extensively, the mechanism of site-specific phosphorylation of Rb remains unclear due to a lack of information on the structural arrangement of Rb and CDK4/6. Here, we have determined and refined to 2.3-A resolution the crystal structure of a gankyrin homolog, the non-ATPase subunit 6 (Nas6p) of the proteasome from yeast. The crystal structure reveals that Nas6p contains seven ankyrin repeats. The number of the repeats is different from that predicted from the primary structure. Nas6p also possesses an unusual curved structure with two acidic regions at the N- and C-terminal regions separated by one basic region, suggesting that it has at least two functional surfaces. The tertiary structure of Nas6p, together with the previous biochemical studies, indicates that the CDK4/6 and Rb binding surfaces of gankyrin are located at the N- and C-terminal regions, respectively, and face the same side of gankyrin. These observations suggest that gankyrin brings Rb and CDK4/6 together through gankyrin-Rb and gankyrin-CDK4/6 interactions and determines the relative positioning of the substrate (Rb) and the enzyme (CDK4/6). Our findings provide mechanistic insight into site-specific phosphorylation of Rb caused by CDK4/6.

  17. Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Young Shin; Angove, Hayley; Brain, Christopher; Chen, Christine Hiu-Tung; Cheng, Hong; Cheng, Robert; Chopra, Rajiv; Chung, Kristy; Congreve, Miles; Dagostin, Claudio; Davis, Deborah J.; Feltell, Ruth; Giraldes, John; Hiscock, Steven D.; Kim, Sunkyu; Kovats, Steven; Lagu, Bharat; Lewry, Kim; Loo, Alice; Lu, Yipin; Luzzio, Michael; Maniara, Wiesia; McMenamin, Rachel; Mortenson, Paul N.; Benning, Rajdeep; O' Reilly, Marc; Rees, David C.; Shen, Junqing; Smith, Troy; Wang, Yaping; Williams, Glyn; Woolford, Alison J. -A.; Wrona, Wojciech; Xu, Mei; Yang, Fan; Howard, Steven

    2012-06-14

    Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

  18. GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium▿

    Science.gov (United States)

    Rojas, Anabel; Kong, Sek Won; Agarwal, Pooja; Gilliss, Brian; Pu, William T.; Black, Brian L.

    2008-01-01

    The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes. PMID:18591257

  19. Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells.

    Science.gov (United States)

    The, Inge; Ruijtenberg, Suzan; Bouchet, Benjamin P; Cristobal, Alba; Prinsen, Martine B W; van Mourik, Tim; Koreth, John; Xu, Huihong; Heck, Albert J R; Akhmanova, Anna; Cuppen, Edwin; Boxem, Mike; Muñoz, Javier; van den Heuvel, Sander

    2015-01-06

    Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased screen in the nematode Caenorhabditis elegans. We found that simultaneous mutation of lin-35, a retinoblastoma (Rb)-related gene, and fzr-1, an orthologue to the APC/C co-activator Cdh1, completely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans. CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 amino terminus, resembling inactivating phosphorylations of the human proteins. In human breast cancer cells, simultaneous knockdown of Rb and FZR1 synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/C(FZR1) activity as an important determinant in response to CDK4/6-inhibitors.

  20. Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy.

    Science.gov (United States)

    Zha, Chuantao; Deng, Wenjia; Fu, Yan; Tang, Shuai; Lan, Xiaojing; Ye, Yan; Su, Yi; Jiang, Lei; Chen, Yi; Huang, Ying; Ding, Jian; Geng, Meiyu; Huang, Min; Wan, Huixin

    2018-03-25

    CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel anticancer agent for further preclinical study. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  1. CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo

    Science.gov (United States)

    Mende, Nicole; Kuchen, Erika E.; Lesche, Mathias; Grinenko, Tatyana; Kokkaliaris, Konstantinos D.; Hanenberg, Helmut; Lindemann, Dirk; Dahl, Andreas; Platz, Alexander; Höfer, Thomas; Calegari, Federico

    2015-01-01

    Maintenance of stem cell properties is associated with reduced proliferation. However, in mouse hematopoietic stem cells (HSCs), loss of quiescence results in a wide range of phenotypes, ranging from functional failure to extensive self-renewal. It remains unknown whether the function of human HSCs is controlled by the kinetics of cell cycle progression. Using human HSCs and human progenitor cells (HSPCs), we report here that elevated levels of CCND1–CDK4 complexes promoted the transit from G0 to G1 and shortened the G1 cell cycle phase, resulting in protection from differentiation-inducing signals in vitro and increasing human leukocyte engraftment in vivo. Further, CCND1–CDK4 overexpression conferred a competitive advantage without impacting HSPC numbers. In contrast, accelerated cell cycle progression mediated by elevated levels of CCNE1–CDK2 led to the loss of functional HSPCs in vivo. Collectively, these data suggest that the transition kinetics through the early cell cycle phases are key regulators of human HSPC function and important for lifelong hematopoiesis. PMID:26150472

  2. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2– advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Corona SP

    2018-02-01

    Full Text Available Silvia Paola Corona,1 Daniele Generali2 1Radiation Oncology Department, Peter MacCallum Cancer Centre, Bentleigh East, VIC, Australia; 2Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy Abstract: Although early breast cancer (BC is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials. Keywords: CDK4/6 inhibitor, abemaciclib, breast cancer, hormone receptor-positive BC, metastatic BC, mBC

  3. Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells

    International Nuclear Information System (INIS)

    Kang, Jian; Sergio, C Marcelo; Sutherland, Robert L; Musgrove, Elizabeth A

    2014-01-01

    Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer

  4. Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma.

    Science.gov (United States)

    Hart, Lori S; Rader, JulieAnn; Raman, Pichai; Batra, Vandana; Russell, Mike R; Tsang, Matthew; Gagliardi, Maria; Chen, Lucy; Martinez, Daniel; Li, Yimei; Wood, Andrew; Kim, Sunkyu; Parasuraman, Sudha; Delach, Scott; Cole, Kristina A; Krupa, Shiva; Boehm, Markus; Peters, Malte; Caponigro, Giordano; Maris, John M

    2017-04-01

    Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies. Results: Sensitivity to binimetinib and ribociclib was inversely related ( r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs. Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR . ©2016 American Association for Cancer Research.

  5. Palbociclib: First CDK4/6 Inhibitor in Clinical Practice for the Treatment of Advanced HR-Positive Breast Cancer.

    Science.gov (United States)

    Ettl, Johannes

    2016-06-01

    Palbociclib is the first inhibitor of the cyclin-dependent kinases (CDK) 4 and 6 to be introduced into clinical practice. Preclinical investigations led to its clinical development in advanced hormone receptor (HR)-positive breast cancer. To date, 2 significant clinical trials have been fully published. In this article, the results of these trials and their clinical relevance for the management of HR-positive advanced breast cancer are discussed.

  6. A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphoma-like lymphoma formation in mice.

    Science.gov (United States)

    Vincent-Fabert, Christelle; Fiancette, Rémi; Rouaud, Pauline; Baudet, Christel; Truffinet, Véronique; Magnone, Virginie; Guillaudeau, Angélique; Cogné, Michel; Dubus, Pierre; Denizot, Yves

    2012-04-01

    Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24C) mice with Myc-3'RR transgenic mice. The Cdk4(R24C) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24C) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24C) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24C) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  7. Mesenchymal cells recruit and regulate T regulatory cells.

    Science.gov (United States)

    Di Ianni, Mauro; Del Papa, Beatrice; De Ioanni, Maria; Moretti, Lorenzo; Bonifacio, Elisabetta; Cecchini, Debora; Sportoletti, Paolo; Falzetti, Franca; Tabilio, Antonio

    2008-03-01

    Despite much investigation into T regulatory cells (Tregs), little is known about the mechanism controlling their recruitment and function. Because multipotent mesenchymal stromal cells (MSCs) exert an immune regulatory function and suppress T-cell proliferation, this in vitro study investigated their role in Treg recruitment and function. Human MSCs and different T cell populations (CD3(+), CD3(+)/CD45RA(+), CD3(+)/CD45RO(+), CD4(+)/CD25(+), CD4(+)/CD25(+)/CD45RO(+), CD4(+)/CD25(+)/CD45RA(+)) from healthy donors were cocultured for up to 15 days. Harvested lymphocytes were analyzed by flow cytometry and FoxP3 and CD127 expressions were measured by real-time polymerase chain reaction. Their regulatory activity was assessed. We demonstrate MSC recruit Tregs from a fraction of CD3(+) and from immunoselected CD3(+)/CD45RA(+) and CD3(+)/CD45RO(+) fractions. After culture with MSCs both immunoselected fractions registered increases in the CD4(+)/CD25(bright)/FoxP3 subset and CD127 expression was downregulated. When purified Treg populations (CD4/CD25(+), CD4/CD25(+)/CD45RA(+), and CD4/CD25(+)/CD45RO(+)) are used in MSC cocultures, they maintain FoxP3 expression and CD127 expression is downregulated. Treg suppressive capacity was maintained in Treg populations that were layered on MSC for up to 15 days while control Tregs lost all suppressive activity after 5 days culture. In conclusion, our study demonstrates that MSCs recruit, regulate, and maintain T-regulatory phenotype and function over time.

  8. Establishment of clonal myogenic cell lines from severely affected dystrophic muscles - CDK4 maintains the myogenic population

    Directory of Open Access Journals (Sweden)

    Stadler Guido

    2011-03-01

    Full Text Available Abstract Background A hallmark of muscular dystrophies is the replacement of muscle by connective tissue. Muscle biopsies from patients severely affected with facioscapulohumeral muscular dystrophy (FSHD may contain few myogenic cells. Because the chromosomal contraction at 4q35 linked to FSHD is thought to cause a defect within myogenic cells, it is important to study this particular cell type, rather than the fibroblasts and adipocytes of the endomysial fibrosis, to understand the mechanism leading to myopathy. Results We present a protocol to establish clonal myogenic cell lines from even severely dystrophic muscle that has been replaced mostly by fat, using overexpression of CDK4 and the catalytic component of telomerase (human telomerase reverse transcriptase; hTERT, and a subsequent cloning step. hTERT is necessary to compensate for telomere loss during in vitro cultivation, while CDK4 prevents a telomere-independent growth arrest affecting CD56+ myogenic cells, but not their CD56- counterpart, in vitro. Conclusions These immortal cell lines are valuable tools to reproducibly study the effect of the FSHD mutation within myoblasts isolated from muscles that have been severely affected by the disease, without the confounding influence of variable amounts of contaminating connective-tissue cells.

  9. PD-0332991, a CDK4/6 Inhibitor, Significantly Prolongs Survival in a Genetically Engineered Mouse Model of Brainstem Glioma

    Science.gov (United States)

    Barton, Kelly L.; Misuraca, Katherine; Cordero, Francisco; Dobrikova, Elena; Min, Hooney D.; Gromeier, Matthias; Kirsch, David G.; Becher, Oren J.

    2013-01-01

    Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas. PMID:24098593

  10. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.

    Directory of Open Access Journals (Sweden)

    Kelly L Barton

    Full Text Available Diffuse intrinsic pontine glioma (DIPG is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG mouse model. We found that PD-0332991 (PD, a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.

  11. Digital expression profiling identifies RUNX2, CDC5L, MDM2, RECQL4, and CDK4 as potential predictive biomarkers for neo-adjuvant chemotherapy response in paediatric osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Martin

    Full Text Available Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for determining a patients' prognosis is measurement of histopathologic tumor necrosis following pre-operative neo-adjuvant chemotherapy. Unfavourable prognosis is indicated by less than 90% estimated necrosis of the tumor. Neither genetic testing nor molecular biomarkers for diagnosis and prognosis have been described for osteosarcomas. We used the novel nanoString mRNA digital expression analysis system to analyse gene expression in 32 patients with sporadic paediatric osteosarcoma. This system used specific molecular barcodes to quantify expression of a set of 17 genes associated with osteosarcoma tumorigenesis. Five genes, from this panel, which encoded the bone differentiation regulator RUNX2, the cell cycle regulator CDC5L, the TP53 transcriptional inactivator MDM2, the DNA helicase RECQL4, and the cyclin-dependent kinase gene CDK4, were differentially expressed in tumors that responded poorly to neo-adjuvant chemotherapy. Analysis of the signalling relationships of these genes, as well as other expression markers of osteosarcoma, indicated that gene networks linked to RB1, TP53, PI3K, PTEN/Akt, myc and RECQL4 are associated with osteosarcoma. The discovery of these networks provides a basis for further experimental studies of role of the five genes (RUNX2, CDC5L, MDM2, RECQL4, and CDK4 in differential response to chemotherapy.

  12. Targeting the AKT/GSK3β/cyclin D1/Cdk4 survival signaling pathway for eradication of tumor radioresistance acquired by fractionated radiotherapy.

    Science.gov (United States)

    Shimura, Tsutomu; Kakuda, Satoshi; Ochiai, Yasushi; Kuwahara, Yoshikazu; Takai, Yoshihiro; Fukumoto, Manabu

    2011-06-01

    Radioresistance is a major cause of treatment failure of radiotherapy (RT) in human cancer. We have recently revealed that acquired radioresistance of tumor cells induced by fractionated radiation is attributable to cyclin D1 overexpression as a consequence of the downregulation of GSK3β-dependent cyclin D1 proteolysis mediated by a constitutively activated serine-threonine kinase, AKT. This prompted us to hypothesize that targeting the AKT/GSK3β/cyclin D1 pathway may improve fractionated RT by suppressing acquired radioresistance of tumor cells. Two human tumor cell lines with acquired radioresistance were exposed to X-rays after incubation with either an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2), or a Cdk4 inhibitor (Cdk4-I). Cells were then subjected to immunoblotting, clonogenic survival assay, cell growth analysis, and cell death analysis with TUNEL and annexin V staining. In vivo radiosensitivity was assessed by growth of human tumors xenografted into nude mice. Treatment with API-2 resulted in downregulation of cyclin D1 expression in cells with acquired radioresistance. Cellular radioresistance disappeared completely both in vitro and in vivo with accompanying apoptosis when treated with API-2. Furthermore, inhibition of cyclin D1/Cdk4 by Cdk4-I was sufficient for abolishing radioresistance. Treatment with either API-2 or Cdk4-I was also effective in suppressing resistance to cis-platinum (II)-diamine-dichloride in the cells with acquired radioresistance. Interestingly, the radiosensitizing effect of API-2 was canceled by overexpression of cyclin D1 whereas Cdk4-I was still able to sensitize cells with cyclin D1 overexpression. Cyclin D1/Cdk4 is a critical target of the AKT survival signaling pathway responsible for tumor radioresistance. Targeting the AKT/GSK3β/cyclin D1/Cdk4 pathway would provide a novel approach to improve fractionated RT and would have an impact on tumor eradication in combination with chemotherapy. Copyright © 2011

  13. Oncogenic Functions of cdK4 and cdK6

    National Research Council Canada - National Science Library

    Grossel, Martha

    1999-01-01

    .... The retinoblastoma protein (pRb) is one negative regulator of cellular proliferation. Many breast cancers retain functional pRb and therefore must use other mechanisms to alleviate the tumor-suppressive function of pRb...

  14. DMPD: Regulation of phagocyte migration and recruitment by Src-family kinases. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18385944 Regulation of phagocyte migration and recruitment by Src-family kinases. B...how Regulation of phagocyte migration and recruitment by Src-family kinases. PubmedID 18385944 Title Regulation of phagocyte migratio

  15. Overcoming Endocrine Resistance in Hormone-Receptor Positive Advanced Breast Cancer-The Emerging Role of CDK4/6 Inhibitors.

    Science.gov (United States)

    O'Sullivan, Ciara C

    Dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may inhibit senescence and promote cellular proliferation. By using various different mechanisms, malignant cells may increase cyclin D-dependent activity. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in breast cancer; making it a rational target for anticancer therapy. To date, three oral highly selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are in various stages of clinical development: PD0332991 (palbociclib), LEE011 (ribociclib) and LY2835219 (abemaciclib). Results from phase I, II and III trials in hormone-receptor (HR)-positive breast cancer have been encouraging, demonstrating convincing efficacy and a tolerable side-effect profile (mainly uncomplicated neutropenia). This article will review the preclinical and clinical development of the CDK4/6i, as well as reviewing the existing preclinical evidence regarding combination of these agents with chemotherapy and other targeted therapies. Future and ongoing clinical trials, which may expand the potential application of these agents, will also be discussed. In summary, CDK4/6i are exciting compounds which may change the therapeutic landscape of HR-positive breast cancer.

  16. p18 inhibits reprogramming through inactivation of Cdk4/6

    OpenAIRE

    Zhu, Shaohua; Cao, Jiani; Sun, Hongyan; Liu, Kun; Li, Yaqiong; Zhao, Tongbiao

    2016-01-01

    Pluripotent stem cells (PSCs), including embryonic and induced pluripotent stem cells (iPSCs), show atypical cell cycle regulation characterized by a high proliferation rate and a shorter G1 phase compared with somatic cells. The mechanisms by which somatic cells remodel their cell cycle to achieve the high proliferation rate of PSCs during reprogramming are unclear. Here we identify that the Ink4 protein p18, which is expressed at high levels in somatic cells but at low levels in PSCs, is a ...

  17. Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells.

    Science.gov (United States)

    Bonelli, Mara A; Digiacomo, Graziana; Fumarola, Claudia; Alfieri, Roberta; Quaini, Federico; Falco, Angela; Madeddu, Denise; La Monica, Silvia; Cretella, Daniele; Ravelli, Andrea; Ulivi, Paola; Tebaldi, Michela; Calistri, Daniele; Delmonte, Angelo; Ampollini, Luca; Carbognani, Paolo; Tiseo, Marcello; Cavazzoni, Andrea; Petronini, Pier Giorgio

    2017-08-01

    Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16 INK4a and p14 ARF , deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

    Directory of Open Access Journals (Sweden)

    Mara A. Bonelli

    2017-08-01

    Full Text Available Malignant pleural mesothelioma (MPM is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991, a highly selective inhibitor of cyclin-dependent kinase (CDK 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

  19. Molecular Mechanism of Enhanced Anticancer Effect of Nanoparticle Formulated LY2835219 via p16-CDK4/6-pRb Pathway in Colorectal Carcinoma Cell Line

    Directory of Open Access Journals (Sweden)

    Xu Tang

    2016-01-01

    Full Text Available LY2835219 is a dual inhibitor to CDK4 and CDK6. This study was to prepare LY2835219-loaded chitosan nanoparticles (CNP/LY and LY2835219-loaded hyaluronic acid-conjugated chitosan nanoparticles (HACNP/LY and revealed their anticancer effect and influence on p16-CDK4/6-pRb pathway against colon cell line. The nanoparticle sizes of CNP/LY and HACNP/LY were approximately 195±39.6 nm and 217±31.1 nm, respectively. The zeta potentials of CNP/LY and HACNP/LY were 37.3±1.5 mV and 30.3±2.2 mV, respectively. And the preparation process showed considerable drug encapsulation efficiency and loading efficiency. LY2835219, CNP/LY, and HACNP/LY inhibited HT29 cell proliferation with 0.68, 0.54, and 0.30 μM of IC50, respectively. G1 phase was arrested by LY2835219 and its formulations. Furthermore, inhibition of CDK4/6 by LY2835219 formulations induced CDK4, CDK6, cyclin D1, and pRb decrease and p16 increase at both protein and mRNA levels. Overall, nanoparticle formulated LY2835219 could enhance the cytotoxicity and cell cycle arrest, and HACNP/LY strengthened the trend furtherly compared to CNP/LY. It is the first time to demonstrate the anticancer effect and mechanism against HT29 by LY2835219 and its nanoparticles. The drug and its nanoparticle formulations delay the cell growth and arrest cell cycle through p16-CDK4/6-pRb pathway, while the nanoparticle formulated LY2835219 could strengthen the process.

  20. Heparan sulphate as a regulator of leukocyte recruitment in inflammation.

    Science.gov (United States)

    Kumar, Archana V; Katakam, Sampath K; Urbanowitz, Ann-Kathrin; Gotte, Martin

    2015-01-01

    A key event in inflammatory disease is the transendothelial recruitment of leukocytes from the circulation to the site of inflammation. Intense research in the past decades indicates that the polyanionic carbohydrate heparan sulphate (HS) modulates multiple steps in the leukocyte recruitment cascade. Leukocyte recruitment is initiated by endothelial cell activation and presentation of chemokines to rolling leukocytes, which, via integrin activation, results in adhesion and diapedesis through the vessel wall. Heparan sulfate proteoglycans (HSPGs) immobilize the chemokines on the luminal endothelial cells, rendering them more robust against mechanical or hydrodynamic perturbations. During inflammation, endothelial HSPGs serve as ligands to L-selectin on leukocytes, transport chemokines in a basolateral to apical direction across the endothelium, and present chemokines at the luminal surface of the endothelium to circulating cells. HSPGs also promote chemokine oligomerization, which influences chemokine receptor signaling. Furthermore, proteoglycans of the syndecan family are involved in modulating integrin-mediated tight adhesion of leukocytes to the endothelium. Creation of a chemokine gradient by a localized chemokine release influences the speed of leukocyte recruitment from the blood to the tissue by attracting crawling neutrophils to optimal sites for transmigration. The directionality of intraluminal crawling is thought to be influenced by both mechanotactic and haptotactic signals, which are modulated by HS-dependent signaling processes. Finally, diapedesis is influenced by HS regarding transendothelial chemokine gradient formation and integrin- CAM interactions, and further enhanced by heparanase-mediated degradation of the endothelial basement membrane. Overall, the multifunctional role of HS in inflammation marks it as a potential target of glycan-centered therapeutic approaches.

  1. NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment.

    Science.gov (United States)

    Hirai, Yugo; Tamura, Miki; Otani, Junji; Ishikawa, Fuyuki

    2016-08-01

    Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase. However, it remains largely unknown how telomerase recruitment is regulated by cell cycle regulators. We show that TPP1 interacts with the cell cycle regulator kinase NEK6 in human cells. We found that NEK6-mediated phosphorylation of TPP1 Ser255 in G2/M phase regulates the association between telomerase activity and TPP1. Furthermore, we found evidence that POT1 negatively regulates TPP1 phosphorylation because the level of Ser255 phosphorylation was elevated when telomeres were elongated by a POT1 mutant lacking its OB-fold domains. Ser255 is located in the intervening region between the telomerase-recruiting OB-fold and the POT1 recruitment domains. Ser255 and the surrounding amino acids are conserved among vertebrates. These observations suggest that a region adjacent to the OB-fold domain of TPP1 is involved in telomere length regulation via telomerase recruitment. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  2. Loss of keratinocytic RXRα combined with activated CDK4 or oncogenic NRAS generates UVB-induced melanomas via loss of p53 and PTEN in the tumor microenvironment.

    Science.gov (United States)

    Coleman, Daniel J; Chagani, Sharmeen; Hyter, Stephen; Sherman, Anna M; Löhr, Christiane V; Liang, Xiaobo; Ganguli-Indra, Gitali; Indra, Arup K

    2015-01-01

    Understanding the molecular mechanisms behind formation of melanoma, the deadliest form of skin cancer, is crucial for improved diagnosis and treatment. One key is to better understand the cross-talk between epidermal keratinocytes and pigment-producing melanocytes. Here, using a bigenic mouse model system combining mutant oncogenic NRAS(Q61K) (constitutively active RAS) or mutant activated CDK4(R24C/R24C) (prevents binding of CDK4 by kinase inhibitor p16(INK4A)) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRα(ep-/-)) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRα(ep-/-) mice are larger in size with higher proliferative capacity, and exhibit enhanced angiogenic properties and increased expression of malignant melanoma markers. Analysis of tumor adjacent normal skin from these mice revealed altered expression of several biomarkers indicative of enhanced melanoma susceptibility, including reduced expression of tumor suppressor p53 and loss of PTEN, with concomitant increase in activated AKT. Loss of epidermal RXRα in combination with UVB significantly enhances invasion of melanocytic cells to draining lymph nodes in bigenic mice expressing oncogenic NRAS(Q61K) compared with controls with functional RXRα. These results suggest a crucial role of keratinocytic RXRα to suppress formation of UVB-induced melanomas and their progression to malignant cancers in the context of driver mutations such as activated CDK4(R24C/R24C) or oncogenic NRAS(Q61K). These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis. ©2014 American Association for Cancer Research.

  3. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

    Science.gov (United States)

    Patnaik, Amita; Rosen, Lee S; Tolaney, Sara M; Tolcher, Anthony W; Goldman, Jonathan W; Gandhi, Leena; Papadopoulos, Kyriakos P; Beeram, Muralidhar; Rasco, Drew W; Hilton, John F; Nasir, Aejaz; Beckmann, Richard P; Schade, Andrew E; Fulford, Angie D; Nguyen, Tuan S; Martinez, Ricardo; Kulanthaivel, Palaniappan; Li, Lily Q; Frenzel, Martin; Cronier, Damien M; Chan, Edward M; Flaherty, Keith T; Wen, Patrick Y; Shapiro, Geoffrey I

    2016-07-01

    We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months. Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681. ©2016 American Association for Cancer Research.

  4. Inflammatory Monocyte Recruitment Is Regulated by Interleukin-23 during Systemic Bacterial Infection

    Science.gov (United States)

    Indramohan, Mohanalaxmi; Sieve, Amy N.; Break, Timothy J.

    2012-01-01

    Listeria monocytogenes is a Gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals and spontaneous abortion in pregnant women. The innate immune response against L. monocytogenes is primarily mediated by neutrophils and monocytes. Interleukin-23 (IL-23) is an important proinflammatory cytokine well known for its role in neutrophil recruitment in various infectious and autoimmune diseases. We have previously shown that IL-23 is required for host resistance against L. monocytogenes and for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ, suggesting that IL-23 may regulate the recruitment/function of another cell type to the spleen. In this study, we show that specific depletion of neutrophils abrogated the differences in bacterial burdens in the livers but not the spleens of C57BL/6 (B6) and IL-23p19 KO mice. Interestingly, L. monocytogenes-infected IL-23p19 KO mice had fewer monocytes in the spleen than B6 mice, as well as a reduction in the monocyte-recruiting chemokines CCL2 and CCL7. Additionally, the overall concentrations of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO•), as well as the percentages and total numbers of monocytes producing TNF-α and NO•, were reduced in IL-23p19 KO mice compared to levels in B6 mice, leading to increased bacterial burdens in the spleens of L. monocytogenes-infected IL-23p19 KO mice. Collectively, our data establish that IL-23 is required for the optimal recruitment of TNF-α- and NO•-producing inflammatory monocytes, thus revealing a novel mechanism by which this proinflammatory cytokine provides protection against bacterial infection. PMID:22966045

  5. Differential recruitment of E3 ubiquitin ligase complexes regulates RET isoform internalization.

    Science.gov (United States)

    Hyndman, Brandy D; Crupi, Mathieu J F; Peng, Susan; Bone, Leslie N; Rekab, Aisha N; Lian, Eric Y; Wagner, Simona M; Antonescu, Costin N; Mulligan, Lois M

    2017-10-01

    The RET receptor tyrosine kinase is implicated in normal development and cancer. RET is expressed as two isoforms, RET9 and RET51, with unique C-terminal tail sequences that recruit distinct protein complexes to mediate signals. Upon activation, RET isoforms are internalized with distinct kinetics, suggesting differences in regulation. Here, we demonstrate that RET9 and RET51 differ in their abilities to recruit E3 ubiquitin ligases to their unique C-termini. RET51, but not RET9, interacts with, and is ubiquitylated by CBL, which is recruited through interactions with the GRB2 adaptor protein. RET51 internalization was not affected by CBL knockout but was delayed in GRB2-depleted cells. In contrast, RET9 ubiquitylation requires phosphorylation-dependent changes in accessibility of key RET9 C-terminal binding motifs that facilitate interactions with multiple adaptor proteins, including GRB10 and SHANK2, to recruit the NEDD4 ubiquitin ligase. We showed that NEDD4-mediated ubiquitylation is required for RET9 localization to clathrin-coated pits and subsequent internalization. Our data establish differences in the mechanisms of RET9 and RET51 ubiquitylation and internalization that may influence the strength and duration of RET isoform signals and cellular outputs.This article has an associated First Person interview with the first authors of the paper. © 2017. Published by The Company of Biologists Ltd.

  6. Mantle cell lymphoma-like lymphomas in c-myc-3'RR/p53+/- mice and c-myc-3'RR/Cdk4R24C mice: differential oncogenic mechanisms but similar cellular origin.

    Science.gov (United States)

    Rouaud, Pauline; Fiancette, Rémi; Vincent-Fabert, Christelle; Magnone, Virginie; Cogné, Michel; Dubus, Pierre; Denizot, Yves

    2012-05-01

    Mantle cell lymphoma (MCL) is a malignant lymphoproliferative B-cell disorder that does not occur spontaneously in mice but experimental mice model have been developed. Recently two different mice models prone to develop MCL-like lymphomas were generated: c-myc-3'RR/Cdk4(R24C) mice and c-myc-3'RR/p53+/- mice. Comparison of their gene expression profiles does not highlight specific differences other than those in relation with their specific mutational status (i.e., Cdk4(R24C) mutation or p53 mutations). We propose that similarly to typical human MCL and its blastoid or cyclin-D1 variants that correspond to the same genetic entity, MCL-like lymphomas of c-myc-3'RR/ p53+/- mice and c-myc-3'RR/Cdk4(R24C) mice represent a spectrum of the same entity.

  7. Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2018-02-01

    Full Text Available Shwachman-Diamond syndrome (SDS is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening. We found that overexpression of disease-associated SBDS mutants or knockdown of SBDS hampered the recruitment of telomerase onto telomeres, while the overall reverse transcriptase activity of telomerase remained unaffected. Moreover, we show that SBDS could specifically bind to TPP1 during the S phase of cell cycle, likely functioning as a stabilizer for TPP1-telomerase interaction. Our findings suggest that SBDS is a telomere-protecting protein that participates in regulating telomerase recruitment.

  8. Topography of calcium phosphate ceramics regulates primary cilia length and TGF receptor recruitment associated with osteogenesis.

    Science.gov (United States)

    Zhang, Jingwei; Dalbay, Melis T; Luo, Xiaoman; Vrij, Erik; Barbieri, Davide; Moroni, Lorenzo; de Bruijn, Joost D; van Blitterswijk, Clemens A; Chapple, J Paul; Knight, Martin M; Yuan, Huipin

    2017-07-15

    The surface topography of synthetic biomaterials is known to play a role in material-driven osteogenesis. Recent studies show that TGFβ signalling also initiates osteogenic differentiation. TGFβ signalling requires the recruitment of TGFβ receptors (TGFβR) to the primary cilia. In this study, we hypothesize that the surface topography of calcium phosphate ceramics regulates stem cell morphology, primary cilia structure and TGFβR recruitment to the cilium associated with osteogenic differentiation. We developed a 2D system using two types of tricalcium phosphate (TCP) ceramic discs with identical chemistry. One sample had a surface topography at micron-scale (TCP-B, with a bigger surface structure dimension) whilst the other had a surface topography at submicron scale (TCP-S, with a smaller surface structure dimension). In the absence of osteogenic differentiation factors, human bone marrow stromal cells (hBMSCs) were more spread on TCP-S than on TCP-B with alterations in actin organization and increased primary cilia prevalence and length. The cilia elongation on TCP-S was similar to that observed on glass in the presence of osteogenic media and was followed by recruitment of transforming growth factor-β RII (p-TGFβ RII) to the cilia axoneme. This was associated with enhanced osteogenic differentiation of hBMSCs on TCP-S, as shown by alkaline phosphatase activity and gene expression for key osteogenic markers in the absence of additional osteogenic growth factors. Similarly, in vivo after a 12-week intramuscular implantation in dogs, TCP-S induced bone formation while TCP-B did not. It is most likely that the surface topography of calcium phosphate ceramics regulates primary cilia length and ciliary recruitment of p-TGFβ RII associated with osteogenesis and bone formation. This bioengineering control of osteogenesis via primary cilia modulation may represent a new type of biomaterial-based ciliotherapy for orthopedic, dental and maxillofacial surgery

  9. Phosphatase-regulated recruitment of the spindle- and kinetochore-associated (Ska complex to kinetochores

    Directory of Open Access Journals (Sweden)

    Sushama Sivakumar

    2017-11-01

    Full Text Available Kinetochores move chromosomes on dynamic spindle microtubules and regulate signaling of the spindle checkpoint. The spindle- and kinetochore-associated (Ska complex, a hexamer composed of two copies of Ska1, Ska2 and Ska3, has been implicated in both roles. Phosphorylation of kinetochore components by the well-studied mitotic kinases Cdk1, Aurora B, Plk1, Mps1, and Bub1 regulate chromosome movement and checkpoint signaling. Roles for the opposing phosphatases are more poorly defined. Recently, we showed that the C terminus of Ska1 recruits protein phosphatase 1 (PP1 to kinetochores. Here we show that PP1 and protein phosphatase 2A (PP2A both promote accumulation of Ska at kinetochores. Depletion of PP1 or PP2A by siRNA reduces Ska binding at kinetochores, impairs alignment of chromosomes to the spindle midplane, and causes metaphase delay or arrest, phenotypes that are also seen after depletion of Ska. Artificial tethering of PP1 to the outer kinetochore protein Nuf2 promotes Ska recruitment to kinetochores, and it reduces but does not fully rescue chromosome alignment and metaphase arrest defects seen after Ska depletion. We propose that Ska has multiple functions in promoting mitotic progression and that kinetochore-associated phosphatases function in a positive feedback cycle to reinforce Ska complex accumulation at kinetochores.

  10. Global regulator SATB1 recruits beta-catenin and regulates T(H2 differentiation in Wnt-dependent manner.

    Directory of Open Access Journals (Sweden)

    Dimple Notani

    2010-01-01

    Full Text Available In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1, the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H2 specific transcription factor that regulates production of T(H2 cytokines and functions as T(H2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+ T cells, suggesting that SATB1 influences T(H2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1, an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H2 cells in a Wnt-dependent manner. SATB1 coordinates T(H2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1

  11. Signaling through MyD88 regulates leukocyte recruitment after brain injury

    DEFF Research Database (Denmark)

    Babcock, Alicia A; Toft-Hansen, Henrik; Owens, Trevor

    2008-01-01

    Injury to the CNS provokes an innate inflammatory reaction that engages infiltrating leukocytes with the capacity to repair and/or exacerbate tissue damage. The initial cues that orchestrate leukocyte entry remain poorly defined. We have used flow cytometry to investigate whether MyD88, an adaptor...... protein that transmits signals from TLRs and receptors for IL-1 and IL-18, regulates leukocyte infiltration into the stab-injured entorhinal cortex (EC) and into sites of axonal degeneration in the denervated hippocampus. We have previously established the kinetics of leukocyte entry into the denervated...... hippocampus. We now show that significant leukocyte entry into the EC occurs within 3-12 h of stab injury. Whereas T cells showed small, gradual increases over 8 days, macrophage infiltration was pronounced and peaked within 12-24 h. MyD88 deficiency significantly reduced macrophage and T cell recruitment...

  12. Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes.

    Science.gov (United States)

    van Ree, Janine H; Nam, Hyun-Ja; Jeganathan, Karthik B; Kanakkanthara, Arun; van Deursen, Jan M

    2016-07-01

    Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis, we engineered mice lacking the PDZ-binding domain (PDZ-BD). Here, we show that the PDZ-BD regulates centrosome movement and that its heterozygous or homozygous deletion promotes aneuploidy and tumour formation. We found that Pten is recruited to pre-mitotic centrosomes in a Plk1-dependent fashion to create a docking site for protein complexes containing the PDZ-domain-containing protein Dlg1 (also known as Sap97) and Eg5 (also known as Kif11), a kinesin essential for centrosome movement and bipolar spindle formation. Docking of Dlg1-Eg5 complexes to Pten depended on Eg5 phosphorylation by the Nek9-Nek6 mitotic kinase cascade and Cdk1. PDZ-BD deletion or Dlg1 ablation impaired loading of Eg5 onto centrosomes and spindle pole motility, yielding asymmetrical spindles that are prone to chromosome missegregation. Collectively, these data demonstrate that Pten, through the Dlg1-binding ability of its PDZ-BD, accumulates phosphorylated Eg5 at duplicated centrosomes to establish symmetrical bipolar spindles that properly segregate chromosomes, and suggest that this function contributes to tumour suppression.

  13. Density regulation in Northeast Atlantic fish populations: Density dependence is stronger in recruitment than in somatic growth.

    Science.gov (United States)

    Zimmermann, Fabian; Ricard, Daniel; Heino, Mikko

    2018-01-30

    Population regulation is a central concept in ecology, yet in many cases its presence and the underlying mechanisms are difficult to demonstrate. The current paradigm maintains that marine fish populations are predominantly regulated by density-dependent recruitment. While it is known that density-dependent somatic growth can be present too, its general importance remains unknown and most practical applications neglect it. This study aimed to close this gap by for the first time quantifying and comparing density dependence in growth and recruitment over a large set of fish populations. We fitted density-dependent models to time-series data on population size, recruitment and age-specific weight from commercially exploited fish populations in the Northeast Atlantic Ocean and the Baltic Sea. Data were standardized to enable a direct comparison within and among populations, and estimated parameters were used to quantify the impact of density regulation on population biomass. Statistically significant density dependence in recruitment was detected in a large proportion of populations (70%), whereas for density dependence in somatic growth the prevalence of density dependence depended heavily on the method (26% and 69%). Despite age-dependent variability, the density dependence in recruitment was consistently stronger among age groups and between alternative approaches that use weight-at-age or weight increments to assess growth. Estimates of density-dependent reduction in biomass underlined these results: 97% of populations with statistically significant parameters for growth and recruitment showed a larger impact of density-dependent recruitment on population biomass. The results reaffirm the importance of density-dependent recruitment in marine fishes, yet they also show that density dependence in somatic growth is not uncommon. Furthermore, the results are important from an applied perspective because density dependence in somatic growth affects productivity and

  14. Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Pranav Gupta

    2018-02-01

    Full Text Available Background/Aims: The overexpression of ATP-Binding Cassette (ABC transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti

  15. Involvement of cyclin D1/CDK4 and pRb mediated by PI3K/AKT pathway activation in Pb2+-induced neuronal death in cultured hippocampal neurons

    International Nuclear Information System (INIS)

    Li Chenchen; Xing Tairan; Tang Mingliang; Yong Wu; Yan Dan; Deng Hongmin; Wang Huili; Wang Ming; Chen Jutao; Ruan Diyun

    2008-01-01

    Lead (Pb) is widely recognized as a neurotoxicant. One of the suggested mechanisms of lead neurotoxicity is apoptotic cell death. And the mechanism by which Pb 2+ causes neuronal death is not well understood. The present study sought to examine the obligate nature of cyclin D1/cyclin-dependent kinase 4 (CDK4), phosphorylation of its substrate retinoblastoma protein (pRb) and its select upstream signal phosphoinositide 3-kinase (PI3K)/AKT pathway in the death of primary cultured rat hippocampal neurons evoked by Pb 2+ . Our data showed that lead treatment of primary hippocampal cultures results in dose-dependent cell death. Inhibition of CDK4 prevented Pb 2+ -induced neuronal death significantly but was incomplete. In addition, we demonstrated that the levels of cyclin D1 and pRb/p107 were increased during Pb 2+ treatment. These elevated expression persisted up to 48 h, returning to control levels after 72 h. We also presented pharmacological and morphological evidences that cyclin D1/CDK4 and pRb/p107 were required for such kind of neuronal death. Addition of the PI3K inhibitor LY294002 (30 μM) or wortmannin (100 nM) significantly rescued the cultured hippocampal neurons from death caused by Pb 2+ . And that Pb 2+ -elicited phospho-AKT (Ser473) participated in the induction of cyclin D1 and partial pRb/p107 expression. These results provide evidences that cell cycle elements play a required role in the death of neurons evoked by Pb 2+ and suggest that certain signaling elements upstream of cyclin D1/CDK4 are modified and/or required for this form of neuronal death

  16. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment.

    Science.gov (United States)

    Dorhoi, Anca; Iannaccone, Marco; Farinacci, Maura; Faé, Kellen C; Schreiber, Jörg; Moura-Alves, Pedro; Nouailles, Geraldine; Mollenkopf, Hans-Joachim; Oberbeck-Müller, Dagmar; Jörg, Sabine; Heinemann, Ellen; Hahnke, Karin; Löwe, Delia; Del Nonno, Franca; Goletti, Delia; Capparelli, Rosanna; Kaufmann, Stefan H E

    2013-11-01

    The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223(–/–) mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223(–/–) animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

  17. Environmental factors regulating the recruitment of walleye Sander vitreus and white bass Morone chrysops in irrigation reservoirs

    Science.gov (United States)

    DeBoer, Jason A.; Pope, Kevin L.; Koupal, Keith D.

    2013-01-01

    Understanding the environmental factors that regulate fish recruitment is essential for effective management of fisheries. Generally, first-year survival, and therefore recruitment, is inherently less consistent in systems with high intra- and interannual variability. Irrigation reservoirs display sporadic patterns of annual drawdown, which can pose a substantial challenge to recruitment of fishes. We developed species-specific models using an 18-year data set compiled from state and federal agencies to investigate variables that regulate the recruitment of walleye Sander vitreus and white bass Morone chrysops in irrigation reservoirs in south-west Nebraska, USA. The candidate model set for walleye included only abiotic variables (water-level elevation, minimum daily air temperature during winter prior to hatching, annual precipitation, spring warming rate and May reservoir discharge), and the candidate model set for white bass included primarily biotic variables (catch per unit effort (CPUE) of black crappie Pomoxis nigromaculatus, CPUE of age-0 walleye, CPUE of bluegill Lepomis macrochirus and CPUE of age-3 and older white bass), each of which had a greater relative importance than the single abiotic variable (minimum daily air temperature during winter after hatching). Our findings improve the understanding of the recruitment of fishes in irrigation reservoirs and the relative roles of abiotic and biotic factors.

  18. Rabaptin5 is recruited to endosomes by Rab4 and Rabex5 to regulate endosome maturation.

    Science.gov (United States)

    Kälin, Simone; Hirschmann, David T; Buser, Dominik P; Spiess, Martin

    2015-11-15

    Rab GTPases control membrane identity, fusion and transport by interaction with effector proteins. Effectors that influence the activation-inactivation cycle of their own or other Rab proteins contribute to the timely conversion of Rab membrane identities. Rab5 and its effector rabaptin5 (Rbpt5, also known as RABEP1) are generally considered the prime example for a positive-feedback loop in which Rab5-GTP recruits Rbpt5 in complex with Rabex5 (also known as RABGEF1), the GDP/GTP exchange factor of Rab5, to early endosomes, thus maintaining the Rab5 membrane identity. By deletion analysis, we found that the membrane recruitment of Rabaptin5 required binding to Rab4 and Rabex5, but not Rab5. Deletion of either one of the two Rab5-binding domains or silencing of Rab5 expression did not affect Rabaptin5 recruitment, but produced giant endosomes with early and late endosomal characteristics. The results contradict the model of feedback activation of Rab5 and instead indicate that Rbpt5 is recruited by both Rabex5 recognizing ubiquitylated cargo and by Rab4 to activate Rab5 in a feed-forward manner. © 2015. Published by The Company of Biologists Ltd.

  19. Topography of calcium phosphate ceramics regulates primary cilia length and TGF receptor recruitment associated with osteogenesis

    NARCIS (Netherlands)

    Zhang, Jingwei; Dalbay, Melis T.; Luo, Xiaoman; Vrij, Erik J.; Barbieri, Davide; Moroni, Lorenzo; de Bruijn, Joost D.; van Blitterswijk, Clemens A.; Chapple, J. Paul; Knight, Martin M.; Yuan, Huipin

    2017-01-01

    The surface topography of synthetic biomaterials is known to play a role in material-driven osteogenesis. Recent studies show that TGFβ signalling also initiates osteogenic differentiation. TGFβ signalling requires the recruitment of TGFβ receptors (TGFβR) to the primary cilia. In this study, we

  20. Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination.

    Science.gov (United States)

    DiMenna, Lauren J; Chaudhuri, Jayanta

    2016-03-01

    The mechanism by which the DNA deaminase activation-induced cytidine deaminase (AID) is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is affected. Here, we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a noncoding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of noncoding transcripts during class switching, and has implications in both B cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1

    Directory of Open Access Journals (Sweden)

    Cornelia Kilchert

    2015-12-01

    Full Text Available In eukaryotic cells, inefficient splicing is surprisingly common and leads to the degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here, we uncover a mechanism by which specific intron-containing transcripts are targeted for nuclear degradation in fission yeast. Sequence elements within these “decay-promoting” introns co-transcriptionally recruit the exosome specificity factor Mmi1, which induces degradation of the unspliced precursor and leads to a reduction in the levels of the spliced mRNA. This mechanism negatively regulates levels of the RNA helicase DDX5/Dbp2 to promote cell survival in response to stress. In contrast, fast removal of decay-promoting introns by co-transcriptional splicing precludes Mmi1 recruitment and relieves negative expression regulation. We propose that decay-promoting introns facilitate the regulation of gene expression. Based on the identification of multiple additional Mmi1 targets, including mRNAs, long non-coding RNAs, and sn/snoRNAs, we suggest a general role in RNA regulation for Mmi1 through transcript degradation.

  2. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation.

    Science.gov (United States)

    Rampalli, Shravanti; Li, LiFang; Mak, Esther; Ge, Kai; Brand, Marjorie; Tapscott, Stephen J; Dilworth, F Jeffrey

    2007-12-01

    Cell-specific patterns of gene expression are established through the antagonistic functions of trithorax group (TrxG) and Polycomb group (PcG) proteins. Several muscle-specific genes have previously been shown to be epigenetically marked for repression by PcG proteins in muscle progenitor cells. Here we demonstrate that these developmentally regulated genes become epigenetically marked for gene expression (trimethylated on histone H3 Lys4, H3K4me3) during muscle differentiation through specific recruitment of Ash2L-containing methyltransferase complexes. Targeting of Ash2L to specific genes is mediated by the transcriptional regulator Mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 MAPK signaling pathway via phosphorylation of Mef2d. Thus, we provide evidence that signaling pathways regulate the targeting of TrxG-mediated epigenetic modifications at specific promoters during cellular differentiation.

  3. α4 integrin is a regulator of leukocyte recruitment after experimental intracerebral hemorrhage.

    Science.gov (United States)

    Hammond, Matthew D; Ambler, William G; Ai, Youxi; Sansing, Lauren H

    2014-08-01

    Intracerebral hemorrhage (ICH) is swiftly followed by an inflammatory response. A key component of this response is the recruitment of leukocytes into the brain, which promotes neurological injury in rodent models. However, the mechanisms by which leukocytes transmigrate across the endothelium into the injured brain are unclear. The present study examines leukocyte adhesion molecules (α4 integrin, L-selectin, and αLβ2 integrin) on 4 leukocyte subtypes to determine which are important for leukocyte recruitment after ICH. We used the blood injection mouse model of ICH, whereby 25 μL of blood was injected into the striatum. Flow cytometry was used to quantify leukocyte populations and adhesion molecule expression in brain and blood. An α4 integrin-blocking antibody was administered to evaluate the contribution of α4 integrin in leukocyte migration and neurological injury. α4 integrin was elevated on all leukocyte populations in brain after ICH, whereas L-selectin was unchanged and αLβ2 was increased only on T cells. Antagonism of α4 resulted in decreased leukocyte transmigration and lessened neurobehavioral disability. α4 integrin is an important cell adhesion molecule involved in neuroinflammation after ICH. © 2014 American Heart Association, Inc.

  4. SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability

    Directory of Open Access Journals (Sweden)

    Chao Huang

    2016-04-01

    Full Text Available Origin recognition complex 2 (ORC2, a subunit of the ORC, is essential for DNA replication initiation in eukaryotic cells. In addition to a role in DNA replication initiation at the G1/S phase, ORC2 has been shown to localize to the centromere during the G2/M phase. Here, we show that ORC2 is modified by small ubiquitin-like modifier 2 (SUMO2, but not SUMO1, at the G2/M phase of the cell cycle. SUMO2-modification of ORC2 is important for the recruitment of KDM5A in order to convert H3K4me3 to H3K4me2, a “permissive” histone marker for α-satellite transcription at the centromere. Persistent expression of SUMO-less ORC2 led to reduced α-satellite transcription and impaired pericentric heterochromatin silencing, which resulted in re-replication of heterochromatin DNA. DNA re-replication eventually activated the DNA damage response, causing the bypass of mitosis and the formation of polyploid cells. Thus, ORC2 sustains genomic stability by recruiting KDM5A to maintain centromere histone methylation in order to prevent DNA re-replication.

  5. Down-regulation of homing receptors: a mechanism for impaired recruitment of human phagocytes in sepsis.

    Science.gov (United States)

    Hasslen, S R; Nelson, R D; Kishimoto, T K; Warren, W E; Ahrenholz, D H; Solem, L D

    1991-05-01

    Receptors known as DREG adhesion molecules on human neutrophils and monocytes provide for homing of these phagocytic leukocytes to sites of inflammation. They mediate the initial adhesive interaction of the leukocytes to vascular endothelial cells and are then shed from the cell surface in response to chemotactic factors and inflammatory mediators. Systemic accumulation of these agents following major injury or sepsis may therefore promote shedding of DREG receptors from circulating leukocytes and impair their recruitment to sites of inflammation. To test this hypothesis, we have analyzed the expression of DREG receptors on neutrophils and monocytes from 25 patients admitted to the Surgical Intensive Care Unit. Receptor expression was measured by flow cytometry of cells stained with murine monoclonal DREG-56 anti-DREG antibody. For 14 nonseptic patients, mean monocyte positivity for DREG was reduced from 64% to 40%. For 11 septic patients, mean neutrophil and monocyte positivity for DREG was reduced from 94% to 82% and 64% to 34%, respectively. These results suggest that monocytes are more affected than neutrophils in vivo by conditions expected to stimulate shedding of DREG and that sepsis promotes shedding of these adherence receptors. Accumulation of DREG-negative monocytes in association with sepsis may be sufficient to impair their recruitment to inflammatory sites and limit their contribution to host defense against infection and tissue repair.

  6. Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

    NARCIS (Netherlands)

    Ree, J.H. van; Nam, H.J.; Jeganathan, K.B.; Kanakkanthara, A.; Deursen, J.M.A. van

    2016-01-01

    Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis, we engineered mice lacking the

  7. Recruitment of EB1, a Master Regulator of Microtubule Dynamics, to the Surface of the Theileria annulata Schizont

    KAUST Repository

    Woods, Kerry L.

    2013-05-09

    The apicomplexan parasite Theileria annulata transforms infected host cells, inducing uncontrolled proliferation and clonal expansion of the parasitized cell population. Shortly after sporozoite entry into the target cell, the surrounding host cell membrane is dissolved and an array of host cell microtubules (MTs) surrounds the parasite, which develops into the transforming schizont. The latter does not egress to invade and transform other cells. Instead, it remains tethered to host cell MTs and, during mitosis and cytokinesis, engages the cell\\'s astral and central spindle MTs to secure its distribution between the two daughter cells. The molecular mechanism by which the schizont recruits and stabilizes host cell MTs is not known. MT minus ends are mostly anchored in the MT organizing center, while the plus ends explore the cellular space, switching constantly between phases of growth and shrinkage (called dynamic instability). Assuming the plus ends of growing MTs provide the first point of contact with the parasite, we focused on the complex protein machinery associated with these structures. We now report how the schizont recruits end-binding protein 1 (EB1), a central component of the MT plus end protein interaction network and key regulator of host cell MT dynamics. Using a range of in vitro experiments, we demonstrate that T. annulata p104, a polymorphic antigen expressed on the schizont surface, functions as a genuine EB1-binding protein and can recruit EB1 in the absence of any other parasite proteins. Binding strictly depends on a consensus SxIP motif located in a highly disordered C-terminal region of p104. We further show that parasite interaction with host cell EB1 is cell cycle regulated. This is the first description of a pathogen-encoded protein to interact with EB1 via a bona-fide SxIP motif. Our findings provide important new insight into the mode of interaction between Theileria and the host cell cytoskeleton. 2013 Woods et al.

  8. The Recruitment of AMP-activated Protein Kinase to Glycogen Is Regulated by Autophosphorylation*

    Science.gov (United States)

    Oligschlaeger, Yvonne; Miglianico, Marie; Chanda, Dipanjan; Scholz, Roland; Thali, Ramon F.; Tuerk, Roland; Stapleton, David I.; Gooley, Paul R.; Neumann, Dietbert

    2015-01-01

    The mammalian AMP-activated protein kinase (AMPK) is an obligatory αβγ heterotrimeric complex carrying a carbohydrate-binding module (CBM) in the β-subunit (AMPKβ) capable of attaching AMPK to glycogen. Nonetheless, AMPK localizes at many different cellular compartments, implying the existence of mechanisms that prevent AMPK from glycogen binding. Cell-free carbohydrate binding assays revealed that AMPK autophosphorylation abolished its carbohydrate-binding capacity. X-ray structural data of the CBM displays the central positioning of threonine 148 within the binding pocket. Substitution of Thr-148 for a phospho-mimicking aspartate (T148D) prevents AMPK from binding to carbohydrate. Overexpression of isolated CBM or β1-containing AMPK in cellular models revealed that wild type (WT) localizes to glycogen particles, whereas T148D shows a diffuse pattern. Pharmacological AMPK activation and glycogen degradation by glucose deprivation but not forskolin enhanced cellular Thr-148 phosphorylation. Cellular glycogen content was higher if pharmacological AMPK activation was combined with overexpression of T148D mutant relative to WT AMPK. In summary, these data show that glycogen-binding capacity of AMPKβ is regulated by Thr-148 autophosphorylation with likely implications in the regulation of glycogen turnover. The findings further raise the possibility of regulated carbohydrate-binding function in a wider variety of CBM-containing proteins. PMID:25792737

  9. The recruitment of AMP-activated protein kinase to glycogen is regulated by autophosphorylation.

    Science.gov (United States)

    Oligschlaeger, Yvonne; Miglianico, Marie; Chanda, Dipanjan; Scholz, Roland; Thali, Ramon F; Tuerk, Roland; Stapleton, David I; Gooley, Paul R; Neumann, Dietbert

    2015-05-01

    The mammalian AMP-activated protein kinase (AMPK) is an obligatory αβγ heterotrimeric complex carrying a carbohydrate-binding module (CBM) in the β-subunit (AMPKβ) capable of attaching AMPK to glycogen. Nonetheless, AMPK localizes at many different cellular compartments, implying the existence of mechanisms that prevent AMPK from glycogen binding. Cell-free carbohydrate binding assays revealed that AMPK autophosphorylation abolished its carbohydrate-binding capacity. X-ray structural data of the CBM displays the central positioning of threonine 148 within the binding pocket. Substitution of Thr-148 for a phospho-mimicking aspartate (T148D) prevents AMPK from binding to carbohydrate. Overexpression of isolated CBM or β1-containing AMPK in cellular models revealed that wild type (WT) localizes to glycogen particles, whereas T148D shows a diffuse pattern. Pharmacological AMPK activation and glycogen degradation by glucose deprivation but not forskolin enhanced cellular Thr-148 phosphorylation. Cellular glycogen content was higher if pharmacological AMPK activation was combined with overexpression of T148D mutant relative to WT AMPK. In summary, these data show that glycogen-binding capacity of AMPKβ is regulated by Thr-148 autophosphorylation with likely implications in the regulation of glycogen turnover. The findings further raise the possibility of regulated carbohydrate-binding function in a wider variety of CBM-containing proteins. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes

    Science.gov (United States)

    Hata, Kenji; Takashima, Rikako; Amano, Katsuhiko; Ono, Koichiro; Nakanishi, Masako; Yoshida, Michiko; Wakabayashi, Makoto; Matsuda, Akio; Maeda, Yoshinobu; Suzuki, Yutaka; Sugano, Sumio; Whitson, Robert H.; Nishimura, Riko; Yoneda, Toshiyuki

    2013-11-01

    Histone modification, a critical step for epigenetic regulation, is an important modulator of biological events. Sox9 is a transcription factor critical for endochondral ossification; however, proof of its epigenetic regulation remains elusive. Here we identify AT-rich interactive domain 5b (Arid5b) as a transcriptional co-regulator of Sox9. Arid5b physically associates with Sox9 and synergistically induces chondrogenesis. Growth of Arid5b-/- mice is retarded with delayed endochondral ossification. Sox9-dependent chondrogenesis is attenuated in Arid5b-deficient cells. Arid5b recruits Phf2, a histone lysine demethylase, to the promoter region of Sox9 target genes and stimulates H3K9me2 demethylation of these genes. In the promoters of chondrogenic marker genes, H3K9me2 levels are increased in Arid5b-/- chondrocytes. Finally, we show that Phf2 knockdown inhibits Sox9-induced chondrocyte differentiation. Our findings establish an epigenomic mechanism of skeletal development, whereby Arid5b promotes chondrogenesis by facilitating Phf2-mediated histone demethylation of Sox9-regulated chondrogenic gene promoters.

  11. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

    Science.gov (United States)

    Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-11-24

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

  12. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

    Science.gov (United States)

    Murakami, Takashi; Singh, Arun S; Kiyuna, Tasuku; Dry, Sarah M; Li, Yunfeng; James, Aaron W; Igarashi, Kentaro; Kawaguchi, Kei; DeLong, Jonathan C; Zhang, Yong; Hiroshima, Yukihiko; Russell, Tara; Eckardt, Mark A; Yanagawa, Jane; Federman, Noah; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2016-07-26

    Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

  13. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

    Science.gov (United States)

    Murakami, Takashi; Singh, Arun S.; Kiyuna, Tasuku; Dry, Sarah M.; Li, Yunfeng; James, Aaron W.; Igarashi, Kentaro; Kawaguchi, Kei; DeLong, Jonathan C.; Zhang, Yong; Hiroshima, Yukihiko; Russell, Tara; Eckardt, Mark A.; Yanagawa, Jane; Federman, Noah; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C.; Hoffman, Robert M.

    2016-01-01

    Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer. PMID:27286459

  14. EFhd2/swiprosin-1 regulates LPS-induced macrophage recruitment via enhancing actin polymerization and cell migration.

    Science.gov (United States)

    Tu, Ye; Zhang, Lichao; Tong, Lingchang; Wang, Yue; Zhang, Su; Wang, Rongmei; Li, Ling; Wang, Zhibin

    2018-02-01

    Macrophage motility is vital in innate immunity, which contributes strategically to the defensive inflammation process. During bacterial infection, lipopolysaccharide (LPS) potently activates the migration of macrophages via the NF-κB/iNOS/c-Src signaling pathway. However, the downstream region of c-Src that participates in macrophage migration is unclear. EFhd2, a novel actin bundling protein, was evaluated for its role in LPS-stimulated macrophage migration in this study. We found that LPS stimulated the up-regulation, tyrosine phosphorylation and membrane translocation of EFhd2 in macrophages. The absence of EFhd2 inhibited the recruitment of macrophages in the lungs of LPS-induced septic mice. LPS-induced macrophage migration was neutralized by the deletion of EFhd2. EFhd2-mediated up-regulation of NFPs (including Rac1/Cdc42, N-WASP/WAVE2 and Arp2/3 complex) induced by LPS could be used to explain the role of EFhd2 in promoting actin polymerization. Furthermore, the purified EFhd2 could directly promote actin polymerization in vitro. Dasatinib, a c-Src specific inhibitor, inhibited the up-regulation of EFhd2 stimulated by LPS. Therefore, our study demonstrated that EFhd2 might be involved in LPS-stimulated macrophage migration, which provides a potential target for LPS-activated c-Src during macrophage mobilization. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

    Directory of Open Access Journals (Sweden)

    Wei Sheng Chia

    Full Text Available p97/Valosin-containing protein (VCP is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD. It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

  16. TIA-1 Self-Multimerization, Phase Separation, and Recruitment into Stress Granules Are Dynamically Regulated by Zn2+

    Directory of Open Access Journals (Sweden)

    Joseph B. Rayman

    2018-01-01

    Full Text Available Summary: Stress granules are non-membranous structures that transiently form in the cytoplasm during cellular stress, where they promote translational repression of non-essential RNAs and modulate cell signaling by sequestering key signal transduction proteins. These and other functions of stress granules facilitate an adaptive cellular response to environmental adversity. A key component of stress granules is the prion-related RNA-binding protein, T cell intracellular antigen-1 (TIA-1. Here, we report that recombinant TIA-1 undergoes rapid multimerization and phase separation in the presence of divalent zinc, which can be reversed by the zinc chelator, TPEN. Similarly, the formation and maintenance of TIA-1-positive stress granules in arsenite-treated cells are inhibited by TPEN. In addition, Zn2+ is released in cells treated with arsenite, before stress granule formation. These findings suggest that Zn2+ is a physiological ligand of TIA-1, acting as a stress-inducible second messenger to promote multimerization of TIA-1 and subsequent localization into stress granules. : Rayman et al. show that Zn2+ is a stress-inducible second messenger that triggers self-multimerization and phase separation of TIA-1 and regulates dynamic recruitment of TIA-1 into stress granules. This mechanism is part of an adaptive cellular response to environmental adversity. Keywords: TIA-1, TIA1, stress granules, cellular stress, functional prion, phase separation, zinc regulation

  17. Site-specific regulation of oral mucosa-recruiting CD8+T cells in a mouse contact allergy model.

    Science.gov (United States)

    Hirunwidchayarat, Worawalun; Furusawa, Emi; Kang, Siwen; Ohno, Tatsukuni; Takeuchi, Shunsuke; Rungsiyanont, Sorasun; Azuma, Miyuki

    2017-09-02

    Contact allergy is a T cell-mediated, delayed-type hypersensitivity generated by contact exposure of an allergen to the skin and mucosal surface. The clinical manifestations of allergic responses between the skin and oral mucosa vary and the differences in immunopathology have not been clarified. We generated hapten-induced contact hypersensitivity (CH) of the buccal mucosa (BM) in parallel studies with ear skin (ES) CH, and observed several characteristic findings of BM CH. The BM challenge induced more rapid and more severe inflammation than the ES challenge, with abundant granulocyte and CD8 + T cell infiltration. However, these inflammatory responses diminished quickly. Recruiting CD8 + T cells in the BM had higher ratios of CD62L - CD44 low-hi memory-type cells, and showed impaired IFN-γ, greater PD-1, and comparable Ki-67 expression, suggesting that the recruiting-proliferating CD8 + T cells were unable to differentiate into effector T cells and converted into exhausted T cells at the local site. This finding may explain the rapid recovery of the BM from severe inflammation. Preferentially greater expression of PD-1 ligand (B7-H1), was observed in the BM epithelium under the peak inflammation, and the absence of B7-H1 further accelerated CH responses, suggesting the occurrence of PD-1:B7-H1-mediated immune regulation at the local site. Our results may facilitate the understanding of the unique features of contact allergies in the oral mucosa, and guide the development of new strategies for control of contact allergy. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The STAR protein QKI-7 recruits PAPD4 to regulate post-transcriptional polyadenylation of target mRNAs.

    Science.gov (United States)

    Yamagishi, Ryota; Tsusaka, Takeshi; Mitsunaga, Hiroko; Maehata, Takaharu; Hoshino, Shin-ichi

    2016-04-07

    Emerging evidence has demonstrated that regulating the length of the poly(A) tail on an mRNA is an efficient means of controlling gene expression at the post-transcriptional level. In early development, transcription is silenced and gene expression is primarily regulated by cytoplasmic polyadenylation. In somatic cells, considerable progress has been made toward understanding the mechanisms of negative regulation by deadenylation. However, positive regulation through elongation of the poly(A) tail has not been widely studied due to the difficulty in distinguishing whether any observed increase in length is due to the synthesis of new mRNA, reduced deadenylation or cytoplasmic polyadenylation. Here, we overcame this barrier by developing a method for transcriptional pulse-chase analysis under conditions where deadenylases are suppressed. This strategy was used to show that a member of the Star family of RNA binding proteins, QKI, promotes polyadenylation when tethered to a reporter mRNA. Although multiple RNA binding proteins have been implicated in cytoplasmic polyadenylation during early development, previously only CPEB was known to function in this capacity in somatic cells. Importantly, we show that only the cytoplasmic isoform QKI-7 promotes poly(A) tail extension, and that it does so by recruiting the non-canonical poly(A) polymerase PAPD4 through its unique carboxyl-terminal region. We further show that QKI-7 specifically promotes polyadenylation and translation of three natural target mRNAs (hnRNPA1, p27(kip1)and β-catenin) in a manner that is dependent on the QKI response element. An anti-mitogenic signal that induces cell cycle arrest at G1 phase elicits polyadenylation and translation of p27(kip1)mRNA via QKI and PAPD4. Taken together, our findings provide significant new insight into a general mechanism for positive regulation of gene expression by post-transcriptional polyadenylation in somatic cells. © The Author(s) 2016. Published by Oxford

  19. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis

    Science.gov (United States)

    McGlashon, Jacob M.; Gorecki, Michelle C.; Kozlowski, Amanda E.; Thirnbeck, Caitlin K.; Markan, Kathleen R.; Leslie, Kirstie L.; Kotas, Maya E.; Potthoff, Matthew J.; Richerson, George B.; Gillum, Matthew P.

    2015-01-01

    Summary Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the central nervous system are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1bf/f/p mice, in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes. PMID:25955206

  20. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4.

    Science.gov (United States)

    Barhoover, Melissa A; Hall, Julie M; Greenlee, William F; Thomas, Russell S

    2010-02-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with constitutive activities and those induced by xenobiotic ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One unexplained cellular role for the AHR is its ability to promote cell cycle progression in the absence of exogenous ligands, whereas treatment with exogenous ligands induces cell cycle arrest. Within the cell cycle, progression from G(1) to S phase is controlled by sequential phosphorylation of the retinoblastoma protein (RB1) by cyclin D-cyclin-dependent kinase (CDK) 4/6 complexes. In this study, the functional interactions between the AHR, CDK4, and cyclin D1 (CCND1) were investigated as a potential mechanism for the cell cycle regulation by the AHR. Time course cell cycle and molecular experiments were performed in human breast cancer cells. The results demonstrated that the AHR and CDK4 interact within the cell cycle, and the interaction was disrupted upon TCDD treatment. The disruption was temporally correlated with G(1) cell cycle arrest and decreased phosphorylation of RB1. Biochemical reconstitution assays using in vitro-translated protein recapitulated the AHR and CDK4 interaction and showed that CCND1 was also part of the complex. In vitro assays for CDK4 kinase activity demonstrated that RB1 phosphorylation by the AHR/CDK4/CCND1 complex was reduced in the presence of TCDD. The results suggest that the AHR interacts in a complex with CDK4 and CCND1 in the absence of exogenous ligands to facilitate cell cycle progression. This interaction is disrupted by exogenous ligands, such as TCDD, to induce G(1) cell cycle arrest.

  1. Community regulation: the relative importance of recruitment and predation intensity of an intertidal community dominant in a seascape context.

    Directory of Open Access Journals (Sweden)

    Gil Rilov

    Full Text Available Predicting the strength and context-dependency of species interactions across multiple scales is a core area in ecology. This is especially challenging in the marine environment, where populations of most predators and prey are generally open, because of their pelagic larval phase, and recruitment of both is highly variable. In this study we use a comparative-experimental approach on small and large spatial scales to test the relationship between predation intensity and prey recruitment and their relative importance in shaping populations of a dominant rocky intertidal space occupier, mussels, in the context of seascape (availability of nearby subtidal reef habitat. Predation intensity on transplanted mussels was tested inside and outside cages and recruitment was measured with standard larval settlement collectors. We found that on intertidal rocky benches with contiguous subtidal reefs in New Zealand, mussel larval recruitment is usually low but predation on recruits by subtidal consumers (fish, crabs is intense during high tide. On nearby intertidal rocky benches with adjacent sandy subtidal habitats, larval recruitment is usually greater but subtidal predators are typically rare and predation is weaker. Multiple regression analysis showed that predation intensity accounts for most of the variability in the abundance of adult mussels compared to recruitment. This seascape-dependent, predation-recruitment relationship could scale up to explain regional community variability. We argue that community ecology models should include seascape context-dependency and its effects on recruitment and species interactions for better predictions of coastal community dynamics and structure.

  2. lncRNA Panct1 Maintains Mouse Embryonic Stem Cell Identity by Regulating TOBF1 Recruitment to Oct-Sox Sequences in Early G1

    DEFF Research Database (Denmark)

    Chakraborty, Debojyoti; Paszkowski-Rogacz, Maciej; Berger, Nicolas

    2017-01-01

    Long noncoding RNAs (lncRNAs) have been implicated in diverse biological processes, including embryonic stem cell (ESC) maintenance. However, their functional mechanisms remain largely undefined. Here, we show that the lncRNA Panct1 regulates the transient recruitment of a putative X......-chromosome-encoded protein A830080D01Rik, hereafter referred to as transient octamer binding factor 1 (TOBF1), to genomic sites resembling the canonical Oct-Sox motif. TOBF1 physically interacts with Panct1 and exhibits a cell-cycle-specific punctate localization in ESCs. At the chromatin level, this correlates with its...... recruitment to promoters of pluripotency genes. Strikingly, mutating an octamer-like motif in Panct1 RNA abrogates the strength of TOBF1 localization and recruitment to its targets. Taken together, our data reveal a tightly controlled spatial and temporal pattern of lncRNA-mediated gene regulation in a cell...

  3. Seasonal regulation of herbivory and nutrient effects on macroalgal recruitment and succession in a Florida coral reef

    Directory of Open Access Journals (Sweden)

    Alain Duran

    2016-11-01

    Full Text Available Herbivory and nutrient enrichment are drivers of benthic dynamics of coral reef macroalgae; however, their impact may vary seasonally. In this study we evaluated the effects of herbivore pressure, nutrient availability and potential propagule supply on seasonal recruitment and succession of macroalgal communities on a Florida coral reef. Recruitment tiles, replaced every three months, and succession tiles, kept in the field for nine months, were established in an ongoing factorial nutrient enrichment-herbivore exclusion experiment. The ongoing experiment had already created very different algal communities across the different herbivory and nutrient treatments. We tracked algal recruitment, species richness, and species abundance through time. Our results show seasonal variation in the effect of herbivory and nutrient availability on recruitment of coral reef macroalgae. In the spring, when there was higher macroalgal species richness and abundance of recruits, herbivory appeared to have more control on macroalgal community structure than did nutrients. In contrast, there was no effect of either herbivory or nutrient enrichment on macroalgal communities on recruitment tiles in cooler seasons. The abundance of recruits on tiles was positively correlated with the abundance of algal in the ongoing, established experiment, suggesting that propagule abundance is likely a strong influence on algal recruitment and early succession. Results of the present study suggest that abundant herbivorous fishes control recruitment and succession of macroalgae, particularly in the warm season when macroalgal growth is higher. However, herbivory appears less impactful on algal recruitment and community dynamics in cooler seasons. Ultimately, our data suggest that the timing of coral mortality (e.g., summer vs. winter mortality and freeing of benthic space may strongly influence the dynamics of algae that colonize open space.

  4. Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC regulates inflammasomes

    Directory of Open Access Journals (Sweden)

    Rojanasakul Yon

    2010-05-01

    Full Text Available Abstract Background The apoptotic speck-like protein containing a caspase recruitment domain (ASC is the essential adaptor protein for caspase 1 mediated interleukin (IL-1β and IL-18 processing in inflammasomes. It bridges activated Nod like receptors (NLRs, which are a family of cytosolic pattern recognition receptors of the innate immune system, with caspase 1, resulting in caspase 1 activation and subsequent processing of caspase 1 substrates. Hence, macrophages from ASC deficient mice are impaired in their ability to produce bioactive IL-1β. Furthermore, we recently showed that ASC translocates from the nucleus to the cytosol in response to inflammatory stimulation in order to promote an inflammasome response, which triggers IL-1β processing and secretion. However, the precise regulation of inflammasomes at the level of ASC is still not completely understood. In this study we identified and characterized three novel ASC isoforms for their ability to function as an inflammasome adaptor. Methods To establish the ability of ASC and ASC isoforms as functional inflammasome adaptors, IL-1β processing and secretion was investigated by ELISA in inflammasome reconstitution assays, stable expression in THP-1 and J774A1 cells, and by restoring the lack of endogenous ASC in mouse RAW264.7 macrophages. In addition, the localization of ASC and ASC isoforms was determined by immunofluorescence staining. Results The three novel ASC isoforms, ASC-b, ASC-c and ASC-d display unique and distinct capabilities to each other and to full length ASC in respect to their function as an inflammasome adaptor, with one of the isoforms even showing an inhibitory effect. Consistently, only the activating isoforms of ASC, ASC and ASC-b, co-localized with NLRP3 and caspase 1, while the inhibitory isoform ASC-c, co-localized only with caspase 1, but not with NLRP3. ASC-d did not co-localize with NLRP3 or with caspase 1 and consistently lacked the ability to function as an

  5. Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo

    Science.gov (United States)

    Lefevre, Pascal; Melnik, Svitlana; Wilson, Nicola; Riggs, Arthur D.; Bonifer, Constanze

    2003-01-01

    Expression of the chicken lysozyme gene is upregulated during macrophage differentiation and reaches its highest level in bacterial lipopolysaccharide (LPS)-stimulated macrophages. This is accompanied by complex alterations in chromatin structure. We have previously shown that chromatin fine-structure alterations precede the onset of gene expression in macrophage precursor cells and mark the lysozyme chromatin domain for expression later in development. To further examine this phenomenon and to investigate the basis for the differentiation-dependent alterations of lysozyme chromatin, we studied the recruitment of transcription factors to the lysozyme locus in vivo at different stages of myeloid differentiation. Factor recruitment occurred in several steps. First, early-acting transcription factors such as NF1 and Fli-1 bound to a subset of enhancer elements and recruited CREB-binding protein. LPS stimulation led to an additional recruitment of C/EBPβ and a significant change in enhancer and promoter structure. Transcription factor recruitment was accompanied by specific changes in histone modification within the lysozyme chromatin domain. Interestingly, we present evidence for a transient interaction of transcription factors with lysozyme chromatin in lysozyme-nonexpressing macrophage precursors, which was accompanied by a partial demethylation of CpG sites. This indicates that a partially accessible chromatin structure of lineage-specific genes is a hallmark of hematopoietic progenitor cells. PMID:12773578

  6. Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer.

    Science.gov (United States)

    Li, Yongtao; Luo, Xiaohe; Guo, Qingxiang; Nie, Yongwei; Wang, Tianqi; Zhang, Chao; Huang, Zhi; Wang, Xin; Liu, Yanhua; Chen, Yanan; Zheng, Jianyu; Yang, Shengyong; Fan, Yan; Xiang, Rong

    2018-04-12

    A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC 50 = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity. Compound 6e induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with 6e showed significant antitumor efficacy. The insight into mechanisms of 6e indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound 6e could be a promising drug candidate for cancer therapy.

  7. Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment.

    Science.gov (United States)

    Wunderlich, Claudia M; Ackermann, P Justus; Ostermann, Anna Lena; Adams-Quack, Petra; Vogt, Merly C; Tran, My-Ly; Nikolajev, Alexei; Waisman, Ari; Garbers, Christoph; Theurich, Sebastian; Mauer, Jan; Hövelmeyer, Nadine; Wunderlich, F Thomas

    2018-04-25

    Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and γδ T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and γδ T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients.

  8. The STAR protein QKI-7 recruits PAPD4 to regulate post-transcriptional polyadenylation of target mRNAs

    OpenAIRE

    Yamagishi, Ryota; Tsusaka, Takeshi; Mitsunaga, Hiroko; Maehata, Takaharu; Hoshino, Shin-ichi

    2016-01-01

    Emerging evidence has demonstrated that regulating the length of the poly(A) tail on an mRNA is an efficient means of controlling gene expression at the post-transcriptional level. In early development, transcription is silenced and gene expression is primarily regulated by cytoplasmic polyadenylation. In somatic cells, considerable progress has been made toward understanding the mechanisms of negative regulation by deadenylation. However, positive regulation through elongation of the poly(A)...

  9. The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

    Directory of Open Access Journals (Sweden)

    Micol Ferro

    Full Text Available Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction prevent full triggering of the TCR signaling cascade.

  10. The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

    Science.gov (United States)

    Ferro, Micol; Savino, Maria Teresa; Ortensi, Barbara; Finetti, Francesca; Genovese, Luca; Masi, Giulia; Ulivieri, Cristina; Benati, Daniela; Pelicci, Giuliana; Baldari, Cosima T

    2011-01-01

    Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade.

  11. The Shc Family Protein Adaptor, Rai, Negatively Regulates T Cell Antigen Receptor Signaling by Inhibiting ZAP-70 Recruitment and Activation

    Science.gov (United States)

    Ferro, Micol; Savino, Maria Teresa; Ortensi, Barbara; Finetti, Francesca; Genovese, Luca; Masi, Giulia; Ulivieri, Cristina; Benati, Daniela; Pelicci, Giuliana; Baldari, Cosima T.

    2011-01-01

    Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps –recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade. PMID:22242145

  12. Cdk-dependent phosphorylation regulates TRF1 recruitment to PML bodies and promotes C-circle production in ALT cells.

    Science.gov (United States)

    Wilson, Florence R; Ho, Angus; Walker, John R; Zhu, Xu-Dong

    2016-07-01

    TRF1, a duplex telomeric DNA binding protein, is implicated in homologous-recombination-based alternative lengthening of telomeres, known as ALT. However, how TRF1 promotes ALT activity has yet to be fully characterized. Here we report that Cdk-dependent TRF1 phosphorylation on T371 acts as a switch to create a pool of TRF1, referred to as (pT371)TRF1, which is recruited to ALT-associated PML bodies (APBs) in S and G2 phases independently of its binding to telomeric DNA. We find that phosphorylation of T371 is essential for APB formation and C-circle production, both of which are hallmarks of ALT. We show that the interaction of (pT371)TRF1 with APBs is dependent upon ATM and homologous-recombination-promoting factors Mre11 and BRCA1. In addition, (pT371)TRF1 interaction with APBs is sensitive to transcription inhibition, which also reduces DNA damage at telomeres. Furthermore, overexpression of RNaseH1 impairs (pT371)TRF1 recruitment to APBs in the presence of campothecin, an inhibitor that prevents topoisomerase I from resolving RNA-DNA hybrids. These results suggest that transcription-associated DNA damage, perhaps arising from processing RNA-DNA hybrids at telomeres, triggers (pT371)TRF1 recruitment to APBs to facilitate ALT activity. © 2016. Published by The Company of Biologists Ltd.

  13. Dynamic regulation of genes involved in mitochondrial DNA replication and transcription during mouse brown fat cell differentiation and recruitment

    DEFF Research Database (Denmark)

    Murholm, Maria; Dixen, Karen; Qvortrup, Klaus

    2009-01-01

    ) and a remarkably higher mitochondrial abundance in brown adipocytes. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a comprehensive characterisation of gene expression linked to mitochondrial DNA replication, transcription and function during white and brown fat cell differentiation in vitro as well as in white...... and brown fat, brown adipose tissue fractions and in selected adipose tissues during cold exposure. We find a massive induction of the majority of such genes during brown adipocyte differentiation and recruitment, e.g. of the mitochondrial transcription factors A (Tfam) and B2 (Tfb2m), whereas only a subset...

  14. RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells.

    Science.gov (United States)

    Suzuki, Takahiro; Shimizu, Yuri; Furuhata, Erina; Maeda, Shiori; Kishima, Mami; Nishimura, Hajime; Enomoto, Saaya; Hayashizaki, Yoshihide; Suzuki, Harukazu

    2017-09-12

    RUNX1 is an essential master transcription factor in hematopoietic development and plays important roles in immune functions. Although the gene regulatory mechanism of RUNX1 has been characterized extensively, the epigenetic role of RUNX1 remains unclear. Here, we demonstrate that RUNX1 contributes DNA demethylation in a binding site-directed manner in human hematopoietic cells. Overexpression analysis of RUNX1 showed the RUNX1-binding site-directed DNA demethylation. The RUNX1-mediated DNA demethylation was also observed in DNA replication-arrested cells, suggesting an involvement of active demethylation mechanism. Coimmunoprecipitation in hematopoietic cells showed physical interactions between RUNX1 and DNA demethylation machinery enzymes TET2, TET3, TDG, and GADD45. Further chromatin immunoprecipitation sequencing revealed colocalization of RUNX1 and TET2 in the same genomic regions, indicating recruitment of DNA demethylation machinery by RUNX1. Finally, methylome analysis revealed significant overrepresentation of RUNX1-binding sites at demethylated regions during hematopoietic development. Collectively, the present data provide evidence that RUNX1 contributes site specificity of DNA demethylation by recruitment of TET and other demethylation-related enzymes to its binding sites in hematopoietic cells.

  15. LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes

    Directory of Open Access Journals (Sweden)

    Peter Draber

    2015-12-01

    Full Text Available Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1 ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC, at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC’s M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.

  16. FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration.

    Science.gov (United States)

    Castiglioni, Alessandra; Corna, Gianfranca; Rigamonti, Elena; Basso, Veronica; Vezzoli, Michela; Monno, Antonella; Almada, Albert E; Mondino, Anna; Wagers, Amy J; Manfredi, Angelo A; Rovere-Querini, Patrizia

    2015-01-01

    Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.

  17. FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration

    Science.gov (United States)

    Castiglioni, Alessandra; Basso, Veronica; Vezzoli, Michela; Monno, Antonella; Almada, Albert E.; Mondino, Anna; Wagers, Amy J.; Manfredi, Angelo A.; Rovere-Querini, Patrizia

    2015-01-01

    Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue. PMID:26039259

  18. FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration.

    Directory of Open Access Journals (Sweden)

    Alessandra Castiglioni

    Full Text Available Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.

  19. Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells

    Science.gov (United States)

    Franks, Tobias M.; McCloskey, Asako; Shokhirev, Maxim Nikolaievich; Benner, Chris; Rathore, Annie; Hetzer, Martin W.

    2017-01-01

    Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML. PMID:29269482

  20. Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells.

    Science.gov (United States)

    Franks, Tobias M; McCloskey, Asako; Shokirev, Maxim Nikolaievich; Benner, Chris; Rathore, Annie; Hetzer, Martin W

    2017-11-15

    Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82-Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML. © 2017 Franks et al.; Published by Cold Spring Harbor Laboratory Press.

  1. Hydrogen Sulfide Attenuates the Recruitment of CD11b+Gr-1+ Myeloid Cells and Regulates Bax/Bcl-2 Signaling in Myocardial Ischemia Injury

    Science.gov (United States)

    Zhang, Youen; Li, Hua; Zhao, Gang; Sun, Aijun; Zong, Nobel C.; Li, Zhaofeng; Zhu, Hongming; Zou, Yunzeng; Yang, Xiangdong; Ge, Junbo

    2014-01-01

    Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b+Gr-1+ myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b+Gr-1+ myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling. PMID:24758901

  2. Neuroplasticity of the Hypothalamic–Pituitary–Adrenal Axis Early in Life Requires Recurrent Recruitment of Stress-Regulating Brain Regions

    OpenAIRE

    Fenoglio, Kristina A.; Chen, Yuncai; Baram, Tallie Z.

    2006-01-01

    An eloquent example of experience-induced neuroplasticity involves the enduring effects of daily “handling” of rat pups on the expression of genes regulating hormonal and behavioral responses to stress. Handling-evoked augmentation of maternal care of pups induces long-lasting reduction of hypothalamic corticotropin releasing hormone (CRH) expression and upregulates hippocampal glucocorticoid receptor levels. These changes promote a lifelong attenuation of hormonal stress responses. We have f...

  3. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase

    OpenAIRE

    Nishiyama, Atsuya; Muraki, Keiko; Saito, Motoki; Ohsumi, Keita; Kishimoto, Takeo; Ishikawa, Fuyuki

    2006-01-01

    Telomeres are regulated by a homeostatic mechanism that includes telomerase and telomeric repeat binding proteins, TRF1 and TRF2. Recently, it has been hypothesized that telomeres assume distinct configurations in a cell-cycle-dependent manner, although direct biochemical evidence is lacking. Here we demonstrated that Xenopus TRF1 (xTRF1) associates with telomere chromatin specifically in mitotic Xenopus egg extracts, and dissociates from it upon mitotic exit. Both the N-terminal TRF-homology...

  4. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase

    Science.gov (United States)

    Nishiyama, Atsuya; Muraki, Keiko; Saito, Motoki; Ohsumi, Keita; Kishimoto, Takeo; Ishikawa, Fuyuki

    2006-01-01

    Telomeres are regulated by a homeostatic mechanism that includes telomerase and telomeric repeat binding proteins, TRF1 and TRF2. Recently, it has been hypothesized that telomeres assume distinct configurations in a cell-cycle-dependent manner, although direct biochemical evidence is lacking. Here we demonstrated that Xenopus TRF1 (xTRF1) associates with telomere chromatin specifically in mitotic Xenopus egg extracts, and dissociates from it upon mitotic exit. Both the N-terminal TRF-homology (TRFH) domain and the linker region connecting the TRFH domain and the C-terminal Myb domain are required for this cell-cycle-dependent association of xTRF1 with chromatin. In contrast, Xenopus TRF2 (xTRF2) associates with chromatin throughout the cell cycle. We showed that Polo-like kinase (Plx1) phosphorylates xTRF1 in vitro. Moreover, the mitotic xTRF1–chromatin association was significantly impaired when Plx1 was immunodepleted from the extracts. Finally, high telomerase activities were detected in association with replicating interphase chromatin compared with mitotic chromatin. These results indicate that telomere chromatin is actively regulated by cell-cycle-dependent processes, and provide an insight for understanding how telomeres undergo DNA metabolisms during the cell cycle. PMID:16424898

  5. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis

    DEFF Research Database (Denmark)

    McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E

    2015-01-01

    Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human...... diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white...... adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating...

  6. Separate and shared sympathetic outflow to white and brown fat coordinately regulates thermoregulation and beige adipocyte recruitment

    Science.gov (United States)

    Nguyen, Ngoc Ly T.; Barr, Candace L.; Ryu, Vitaly; Cao, Qiang; Bartness, Timothy J.

    2017-01-01

    White adipose tissue (WAT) and brown adipose tissue (BAT) are innervated and regulated by the sympathetic nervous system (SNS). It is not clear, however, whether there are shared or separate central SNS outflows to WAT and BAT that regulate their function. We injected two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer, with unique fluorescent reporters into interscapular BAT (IBAT) and inguinal WAT (IWAT) of the same Siberian hamsters to define SNS pathways to both. To test the functional importance of SNS coordinated control of BAT and WAT, we exposed hamsters with denervated SNS nerves to IBAT to 4°C for 16–24 h and measured core and fat temperatures and norepinephrine turnover (NETO) and uncoupling protein 1 (UCP1) expression in fat tissues. Overall, there were more SNS neurons innervating IBAT than IWAT across the neuroaxis. However, there was a greater percentage of singly labeled IWAT neurons in midbrain reticular nuclei than singly labeled IBAT neurons. The hindbrain had ~30–40% of doubly labeled neurons while the forebrain had ~25% suggesting shared SNS circuitry to BAT and WAT across the brain. The raphe nucleus, a key region in thermoregulation, had ~40% doubly labeled neurons. Hamsters with IBAT SNS denervation maintained core body temperature during acute cold challenge and had increased beige adipocyte formation in IWAT. They also had increased IWAT NETO, temperature, and UCP1 expression compared with intact hamsters. These data provide strong neuroanatomical and functional evidence of WAT and BAT SNS cross talk for thermoregulation and beige adipocyte formation. PMID:27881398

  7. PI 3 kinase related kinases-independent proteolysis of BRCA1 regulates Rad51 recruitment during genotoxic stress in human cells.

    Directory of Open Access Journals (Sweden)

    Ian Hammond-Martel

    2010-11-01

    Full Text Available The function of BRCA1 in response to ionizing radiation, which directly generates DNA double strand breaks, has been extensively characterized. However previous investigations have produced conflicting data on mutagens that initially induce other classes of DNA adducts. Because of the fundamental and clinical importance of understanding BRCA1 function, we sought to rigorously evaluate the role of this tumor suppressor in response to diverse forms of genotoxic stress.We investigated BRCA1 stability and localization in various human cells treated with model mutagens that trigger different DNA damage signaling pathways. We established that, unlike ionizing radiation, either UVC or methylmethanesulfonate (MMS (generating bulky DNA adducts or alkylated bases respectively induces a transient downregulation of BRCA1 protein which is neither prevented nor enhanced by inhibition of PIKKs. Moreover, we found that the proteasome mediates early degradation of BRCA1, BARD1, BACH1, and Rad52 implying that critical components of the homologous recombination machinery need to be functionally abrogated as part of the early response to UV or MMS. Significantly, we found that inhibition of BRCA1/BARD1 downregulation is accompanied by the unscheduled recruitment of both proteins to chromatin along with Rad51. Consistently, treatment of cells with MMS engendered complete disassembly of Rad51 from pre-formed ionizing radiation-induced foci. Following the initial phase of BRCA1/BARD1 downregulation, we found that the recovery of these proteins in foci coincides with the formation of RPA and Rad51 foci. This indicates that homologous recombination is reactivated at later stage of the cellular response to MMS, most likely to repair DSBs generated by replication blocks.Taken together our results demonstrate that (i the stabilities of BRCA1/BARD1 complexes are regulated in a mutagen-specific manner, and (ii indicate the existence of mechanisms that may be required to

  8. Recruitment of a ribosomal release factor for light- and stress-dependent regulation of petB transcript stability in Arabidopsis chloroplasts.

    Science.gov (United States)

    Stoppel, Rhea; Lezhneva, Lina; Schwenkert, Serena; Torabi, Salar; Felder, Susanne; Meierhoff, Karin; Westhoff, Peter; Meurer, Jörg

    2011-07-01

    Land plant genomes encode four functional ribosomal peptide chain release factors (Prf) of eubacterial origin, two (PrfA and PrfB homologs) for each endosymbiotic organelle. Formerly, we have shown that the Arabidopsis thaliana chloroplast-localized PrfB homolog, PrfB1, is required not only for termination of translation but also for stabilization of UGA stop codon-containing chloroplast transcripts. A previously undiscovered PrfB-like protein, PrfB3, is localized to the chloroplast stroma in a petB RNA-containing complex and found only in vascular plants. Highly conserved positions of introns unequivocally indicate that PrfB3 arose from a duplication of PrfB1. Notably, PrfB3 is lacking the two most important tripeptide motifs characteristic for all eubacterial and organellar PrfB homologs described so far: the stop codon recognition motif SPF and the catalytic center GGQ for peptidyl-tRNA hydrolysis. Complementation studies, as well as functional and molecular analyses of two allelic mutations in Arabidopsis, both of which lead to a specific deficiency of the cytochrome b₆f complex, revealed that PrfB3 is essentially required for photoautotrophic growth. Plastid transcript, polysome, and translation analyses indicate that PrfB3 has been recruited in vascular plants for light- and stress-dependent regulation of stability of 3' processed petB transcripts to adjust cytochrome b₆ levels.

  9. Recruitment of a Ribosomal Release Factor for Light- and Stress-Dependent Regulation of petB Transcript Stability in Arabidopsis Chloroplasts[W][OA

    Science.gov (United States)

    Stoppel, Rhea; Lezhneva, Lina; Schwenkert, Serena; Torabi, Salar; Felder, Susanne; Meierhoff, Karin; Westhoff, Peter; Meurer, Jörg

    2011-01-01

    Land plant genomes encode four functional ribosomal peptide chain release factors (Prf) of eubacterial origin, two (PrfA and PrfB homologs) for each endosymbiotic organelle. Formerly, we have shown that the Arabidopsis thaliana chloroplast-localized PrfB homolog, PrfB1, is required not only for termination of translation but also for stabilization of UGA stop codon-containing chloroplast transcripts. A previously undiscovered PrfB-like protein, PrfB3, is localized to the chloroplast stroma in a petB RNA-containing complex and found only in vascular plants. Highly conserved positions of introns unequivocally indicate that PrfB3 arose from a duplication of PrfB1. Notably, PrfB3 is lacking the two most important tripeptide motifs characteristic for all eubacterial and organellar PrfB homologs described so far: the stop codon recognition motif SPF and the catalytic center GGQ for peptidyl-tRNA hydrolysis. Complementation studies, as well as functional and molecular analyses of two allelic mutations in Arabidopsis, both of which lead to a specific deficiency of the cytochrome b6f complex, revealed that PrfB3 is essentially required for photoautotrophic growth. Plastid transcript, polysome, and translation analyses indicate that PrfB3 has been recruited in vascular plants for light- and stress-dependent regulation of stability of 3′ processed petB transcripts to adjust cytochrome b6 levels. PMID:21771930

  10. 5 CFR 330.402 - Direct recruitment.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Direct recruitment. 330.402 Section 330.402 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS RECRUITMENT, SELECTION, AND PLACEMENT (GENERAL) Positions Restricted to Preference Eligibles § 330.402 Direct recruitment...

  11. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

    Science.gov (United States)

    Kim, Hyunsoo; Huang, Wei; Jiang, Xiuli; Pennicooke, Brenton; Park, Peter J.; Johnson, Mark D.

    2010-01-01

    Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways. PMID:20080666

  12. Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis.

    Science.gov (United States)

    Sun, Zhiguo; Jha, Hem Chandra; Robertson, Erle S

    2015-10-01

    Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. During latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  13. Specific CDK4/6 inhibition in breast cancer

    DEFF Research Database (Denmark)

    Polk, Anne; Kolmos, Ida Lykke; Kümler, Iben

    2016-01-01

    BACKGROUND: Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-dependent kinase-retinoblastoma (CDK-Rb) pathway are common in breast cancer (BC). Consequently, inhibition of this pathway is an attractive therapeutic strategy. The present review addresses efficacy...

  14. Role of CDK4 in Breast Development and Cancer

    Science.gov (United States)

    2008-04-01

    fixed with a mixture (1:3) of glacial acetic acid /ethanol, hydrated, stained with 0.2% carmine and 0.5% AlK(SO4)2, dehydrated in graded solutions of...ethanol, and cleared in toluene and methyl salicylate as described previously (14). Carmine-stained or formalin-fixedmammary glands were also routinely

  15. Tyrosine kinase Btk regulates E-selectin–mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways

    Science.gov (United States)

    Mueller, Helena; Stadtmann, Anika; Van Aken, Hugo; Hirsch, Emilio; Wang, Demin; Ley, Klaus

    2010-01-01

    Selectins mediate leukocyte rolling, trigger β2-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)–dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) γ2– and phosphoinositide 3-kinase (PI3K) γ–dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP3), and inducing E-selectin–mediated slow rolling. Inhibition of this signal-transduction pathway diminished Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk−/− and Plcg2−/− mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement. PMID:20167705

  16. Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis.

    Science.gov (United States)

    Wang, Yaju; Shankar, Shilpa Rani; Kher, Devaki; Ling, Belinda Mei Tze; Taneja, Reshma

    2013-06-14

    Sumoylation is an important post-translational modification that alters the activity of many transcription factors. However, the mechanisms that link sumoylation to alterations in chromatin structure, which culminate in tissue specific gene expression, are not fully understood. In this study, we demonstrate that SUMO modification of the transcription factor Sharp-1 is required for its full transcriptional repression activity and function as an inhibitor of skeletal muscle differentiation. Sharp-1 is modified by sumoylation at two conserved lysine residues 240 and 255. Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. Interestingly, sumoylation acts as a signal for recruitment of the co-repressor G9a. Thus, enrichment of G9a, and histone H3 lysine 9 dimethylation (H3K9me2), a signature of G9a activity, is dramatically reduced at muscle promoters in cells expressing sumoylation-defective Sharp-1. Our findings demonstrate how sumoylation of Sharp-1 exerts an impact on chromatin structure and transcriptional repression of muscle gene expression through recruitment of G9a.

  17. Sumoylation of the Basic Helix-Loop-Helix Transcription Factor Sharp-1 Regulates Recruitment of the Histone Methyltransferase G9a and Function in Myogenesis*

    Science.gov (United States)

    Wang, Yaju; Shankar, Shilpa Rani; Kher, Devaki; Ling, Belinda Mei Tze; Taneja, Reshma

    2013-01-01

    Sumoylation is an important post-translational modification that alters the activity of many transcription factors. However, the mechanisms that link sumoylation to alterations in chromatin structure, which culminate in tissue specific gene expression, are not fully understood. In this study, we demonstrate that SUMO modification of the transcription factor Sharp-1 is required for its full transcriptional repression activity and function as an inhibitor of skeletal muscle differentiation. Sharp-1 is modified by sumoylation at two conserved lysine residues 240 and 255. Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. Interestingly, sumoylation acts as a signal for recruitment of the co-repressor G9a. Thus, enrichment of G9a, and histone H3 lysine 9 dimethylation (H3K9me2), a signature of G9a activity, is dramatically reduced at muscle promoters in cells expressing sumoylation-defective Sharp-1. Our findings demonstrate how sumoylation of Sharp-1 exerts an impact on chromatin structure and transcriptional repression of muscle gene expression through recruitment of G9a. PMID:23637228

  18. T-Cadherin Expression in Melanoma Cells Stimulates Stromal Cell Recruitment and Invasion by Regulating the Expression of Chemokines, Integrins and Adhesion Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Rubina, Kseniya A., E-mail: rkseniya@mail.ru; Surkova, Ekaterina I.; Semina, Ekaterina V.; Sysoeva, Veronika Y.; Kalinina, Natalia I. [Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av., 31/5, Moscow 119192 (Russian Federation); Poliakov, Alexei A. [Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA (United Kingdom); Treshalina, Helena M. [Federal State Budgetary Scietific Institution «N.N. Blokhin Russian Cancer Research Center» (FSBSI “N.N.Blokhin RCRC”), Kashirskoe Shosse 24, Moscow 115478 (Russian Federation); Tkachuk, Vsevolod A. [Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av., 31/5, Moscow 119192 (Russian Federation)

    2015-07-21

    T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate that T-cadherin overexpression leads to the increase in the expression of anti-angiogenic molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells.

  19. Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline.

    Science.gov (United States)

    Fan, Xueping; Labrador, Juan Pablo; Hing, Huey; Bashaw, Greg J

    2003-09-25

    Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Here we present evidence that the SH3-SH2 adaptor protein Dreadlocks (Dock), the p21-activated serine-threonine kinase (Pak), and the Rac1/Rac2/Mtl small GTPases can function during Robo repulsion. Loss-of-function and genetic interaction experiments suggest that limiting the function of Dock, Pak, or Rac partially disrupts Robo repulsion. In addition, Dock can directly bind to Robo's cytoplasmic domain, and the association of Dock and Robo is enhanced by stimulation with Slit. Furthermore, Slit stimulation can recruit a complex of Dock and Pak to the Robo receptor and trigger an increase in Rac1 activity. These results provide a direct physical link between the Robo receptor and an important cytoskeletal regulatory protein complex and suggest that Rac can function in both attractive and repulsive axon guidance.

  20. G protein-coupled receptors regulate Na+,K+-ATPase activity and endocytosis by modulating the recruitment of adaptor protein 2 and clathrin

    Science.gov (United States)

    Ogimoto, Goichi; Yudowski, Guillermo A.; Barker, Christopher J.; Köhler, Martin; Katz, Adrian I.; Féraille, Eric; Pedemonte, Carlos H.; Berggren, Per-Olof; Bertorello, Alejandro M.

    2000-01-01

    Inhibition of Na+,K+-ATPase (NKA) activity in renal epithelial cells by activation of G protein-coupled receptors is mediated by phosphorylation of the catalytic α-subunit followed by endocytosis of active molecules. We examined whether agonists that counteract this effect do so by dephosphorylation of the α-subunit or by preventing its internalization through a direct interaction with the endocytic network. Oxymetazoline counteracted the action of dopamine on NKA activity, and this effect was achieved not by preventing α-subunit phosphorylation, but by impaired endocytosis of α-subunits into clathrin vesicles and early and late endosomes. Dopamine-induced inhibition of NKA activity and α-subunit endocytosis required the interaction of adaptor protein 2 (AP-2) with the catalytic α-subunit. Phosphorylation of the α-subunit is essential because dopamine failed to promote such interaction in cells lacking the protein kinase C phosphorylation residue (S18A). Confocal microscopy confirmed that oxymetazoline prevents incorporation of NKA molecules into clathrin vesicles by inhibiting the ability of dopamine to recruit clathrin to the plasma membrane. Dopamine decreased the basal levels of inositol hexakisphosphate (InsP6), whereas oxymetazoline prevented this effect. Similar increments (above basal) in the concentration of InsP6 induced by oxymetazoline prevented AP-2 binding to the NKA α-subunit in response to dopamine. In conclusion, inhibition of NKA activity can be reversed by preventing its endocytosis without altering the state of α-subunit phosphorylation; increased InsP6 in response to G protein-coupled receptor signals blocks the recruitment of AP-2 and thereby clathrin-dependent endocytosis of NKA. PMID:10716725

  1. Seminal Fluid Regulates Accumulation of FOXP3(+) Regulatory T Cells in the Preimplantation Mouse Uterus Through Expanding the FOXP3(+) Cell Pool and CCL19-Mediated Recruitment

    NARCIS (Netherlands)

    Guerin, Leigh R.; Moldenhauer, Lachlan M.; Prins, Jelmer R.; Bromfield, John J.; Hayball, John D.; Robertson, Sarah A.

    Regulatory T (Treg) cells facilitate maternal immune tolerance of the semiallogeneic conceptus in early pregnancy, but the origin and regulation of these cells at embryo implantation is unclear. During the preimplantation period, factors in the seminal fluid delivered at coitus cause expansion of a

  2. Hydrogen sulfide attenuates the recruitment of CD11b⁺Gr-1⁺ myeloid cells and regulates Bax/Bcl-2 signaling in myocardial ischemia injury.

    Science.gov (United States)

    Zhang, Youen; Li, Hua; Zhao, Gang; Sun, Aijun; Zong, Nobel C; Li, Zhaofeng; Zhu, Hongming; Zou, Yunzeng; Yang, Xiangdong; Ge, Junbo

    2014-04-24

    Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b(+)Gr-1(+) myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b(+)Gr-1(+) myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b(+)Gr-1(+) myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling.

  3. E-recruitment

    DEFF Research Database (Denmark)

    Holm, Anna

    2012-01-01

    E-recruitment, also known as online or web-based recruitment, is little discussed in research from an organizational perspective. The purpose of this chapter is therefore to analyze and discuss the process of e-recruitment, its key constituents and organizing principles. In doing so I draw...

  4. Modifications in cell cycle kinetics and in expression of G1 phase-regulating proteins in human amniotic cells after exposure to electromagnetic fields and ionizing radiation.

    Science.gov (United States)

    Lange, S; Viergutz, T; Simkó, M

    2004-10-01

    Low-frequency electromagnetic fields are suspected of being involved in carcinogenesis, particularly in processes that could be related to cancer promotion. Because development of cancer is associated with deregulated cell growth and we previously observed a magnetic field-induced decrease in DNA synthesis [Lange et al. (2002) Alterations in the cell cycle and in the protein level of cyclin D1p, 21CIP1, and p16INK4a after exposure to 50 HZ. MF in human cells. Radiat. Environ. Biophys.41, 131], this study aims to document the influence of 50 Hz, 1 mT magnetic fields (MF), with or without initial gamma-ionizing radiation (IR), on the following cell proliferation-relevant parameters in human amniotic fluid cells (AFC): cell cycle distribution, expression of the G1 phase-regulating proteins Cdk4, cyclin D1, p21CIP1 and p16INK4a, and Cdk4 activity. While IR induced a G1 delay and a dose-dependent G2 arrest, no discernible changes in cell cycle kinetics were observed due to MF exposure. However, a significant decrease in the protein expression of cyclin D1 and an increase in p21CIP1- and p16INK4a-expression could be detected after exposure to MF alone. IR-exposure caused an augmentation of p21CIP1- and p16INK4a- levels as well, but did not alter cyclin D1 expression. A slight diminution of Cdk4 activity was noticed after MF exposure only, indicating that Cdk4 appears not to act as a mediator of MF- or IR-induced changes in the cell cycle of AFC cells. Co-exposure to MF/IR affected neither cell cycle distribution nor protein expression or kinase activity additionally or synergistically, and therefore MF seems not to modify the mutagenic potency of IR.

  5. Systematic Identification of Proteins Binding to Chromatin-Embedded Ubiquitylated H2B Reveals Recruitment of SWI/SNF to Regulate Transcription

    Directory of Open Access Journals (Sweden)

    Efrat Shema-Yaacoby

    2013-08-01

    Full Text Available Chromatin posttranslational modifications (PTMs, including monoubiquitylation of histone H2B on lysine 120 (H2Bub1, play a major role in regulating genome functions. To elucidate the molecular mechanisms of H2Bub1 activity, a chromatin template uniformly containing H2Bub1 was used as an affinity matrix to identify preferentially interacting human proteins. Over 90 such factors were found, including proteins and protein complexes associated with transcription, RNA posttranscriptional modifications, and DNA replication and repair. Notably, we found that the SWI/SNF chromatin remodeling complex associates preferentially with H2Bub1-rich chromatin. Moreover, SWI/SNF is required for optimal transcription of a subset of genes that are selectively dependent on H2Bub1. Our findings substantially expand the known H2Bub1 interactome and provide insights into the functions of this PTM in mammalian gene regulation.

  6. Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration

    Science.gov (United States)

    Wu, Jui-Chung; Chen, Yu-Chen; Kuo, Chih-Ting; Wenshin Yu, Helen; Chen, Yin-Quan; Chiou, Arthur; Kuo, Jean-Cheng

    2015-01-01

    Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration. PMID:26681405

  7. p37/UBXN2B regulates spindle orientation by limiting cortical NuMA recruitment via PP1/Repo-Man.

    Science.gov (United States)

    Lee, Byung Ho; Schwager, Francoise; Meraldi, Patrick; Gotta, Monica

    2018-02-05

    Spindle orientation determines the axis of division and is crucial for cell fate, tissue morphogenesis, and the development of an organism. In animal cells, spindle orientation is regulated by the conserved Gαi-LGN-NuMA complex, which targets the force generator dynein-dynactin to the cortex. In this study, we show that p37/UBXN2B, a cofactor of the p97 AAA ATPase, regulates spindle orientation in mammalian cells by limiting the levels of cortical NuMA. p37 controls cortical NuMA levels via the phosphatase PP1 and its regulatory subunit Repo-Man, but it acts independently of Gαi, the kinase Aurora A, and the phosphatase PP2A. Our data show that in anaphase, when the spindle elongates, PP1/Repo-Man promotes the accumulation of NuMA at the cortex. In metaphase, p37 negatively regulates this function of PP1, resulting in lower cortical NuMA levels and correct spindle orientation. © 2018 Lee et al.

  8. The Recruitment Process:

    DEFF Research Database (Denmark)

    Holm, Anna

    The aim of this research was to determine whether the introduction of e-recruitment has an impact on the process and underlying tasks, subtasks and activities of recruitment. Three large organizations with well-established e-recruitment practices were included in the study. The three case studies......, which were carried out in Denmark in 2008-2009 using qualitative research methods, revealed changes in the sequence, divisibility and repetitiveness of a number of recruitment tasks and subtasks. The new recruitment process design was identified and presented in the paper. The study concluded...... that the main task of the process shifted from processing applications to communicating with candidates....

  9. E-recruitment

    DEFF Research Database (Denmark)

    Holm, Anna B.

    2012-01-01

    Up to now, there has been little research on the impact of e-recruitment on the recruitment process as a whole. The present study fills part of this gap by investigating the effect of e-recruitment on the design of the recruitment process. Three explorative case studies were carried out in three...... tasks and subtasks. For management, the main task is now that of communicating with candidates. In addition, a new on-going task of maintaining a corporate career website has become an integral part of the new recruitment process. The new design is presented in the following, and its implications...

  10. Regulation of the cell cycle by irradiation

    International Nuclear Information System (INIS)

    Akashi, Makoto

    1995-01-01

    The molecular mechanism of cell proliferation is extremely complex; deregulation results in neoplastic transformation. In eukaryotes, proliferation of cells is finely regulated through the cell cycle. Studies have shown that the cell cycle is regulated by s series of enzymes known as cyclin-dependent kinases (CDKs). The activities of CDKs are controlled by their association with regulatory subunits, cyclins; the expression of cyclins and the activation of the different cyclin-CDK complexes are required for the cell to cycle. Thus, the cell cycle is regulated by activating and inhibiting phosphorylation of the CDK subunits and this program has internal check points at different stages of the cell cycle. When cells are exposed to external insults such as DNA damaging agents, negative regulation of the cell cycle occurs; arrest in either G1 or G2 stage is induced to prevent the cells from prematurely entering into the next stage before DNA is repaired. Recently, a potent inhibitor of CDKs, which inhibits the phosphorylation of retinoblastoma susceptibility (Rb) gene product by cyclin A-CDK2, cyclin E-CDK2, cyclin D1-CDK4, and cyclin D2-CDK4 complexes has been identified. This protein named WAF1, Sdi1, Cip1, or p21 (a protein of Mr 21,000) contains a p53-binding site in its promoter and studies have reported that the expression of WAF1 was directly regulated by p53; cells with loss of p53 activity due to mutational alteration were unable to induce WAF1. This chapter will be focused on the mechanisms of the cell cycle including inhibitors of CDKs, and the induction of WAF1 by irradiation through a pathway independent of p53 will be also described. (author)

  11. Regulation of the cell cycle by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Akashi, Makoto [National Inst. of Radiological Sciences, Chiba (Japan)

    1995-12-01

    The molecular mechanism of cell proliferation is extremely complex; deregulation results in neoplastic transformation. In eukaryotes, proliferation of cells is finely regulated through the cell cycle. Studies have shown that the cell cycle is regulated by s series of enzymes known as cyclin-dependent kinases (CDKs). The activities of CDKs are controlled by their association with regulatory subunits, cyclins; the expression of cyclins and the activation of the different cyclin-CDK complexes are required for the cell to cycle. Thus, the cell cycle is regulated by activating and inhibiting phosphorylation of the CDK subunits and this program has internal check points at different stages of the cell cycle. When cells are exposed to external insults such as DNA damaging agents, negative regulation of the cell cycle occurs; arrest in either G1 or G2 stage is induced to prevent the cells from prematurely entering into the next stage before DNA is repaired. Recently, a potent inhibitor of CDKs, which inhibits the phosphorylation of retinoblastoma susceptibility (Rb) gene product by cyclin A-CDK2, cyclin E-CDK2, cyclin D1-CDK4, and cyclin D2-CDK4 complexes has been identified. This protein named WAF1, Sdi1, Cip1, or p21 (a protein of Mr 21,000) contains a p53-binding site in its promoter and studies have reported that the expression of WAF1 was directly regulated by p53; cells with loss of p53 activity due to mutational alteration were unable to induce WAF1. This chapter will be focused on the mechanisms of the cell cycle including inhibitors of CDKs, and the induction of WAF1 by irradiation through a pathway independent of p53 will be also described. (author)

  12. The cell cycle regulators p15, p16, p18 and p19 : functions and regulation during normal cell cycle and in multistep carcinogenesis

    OpenAIRE

    Thullberg, Minna

    2000-01-01

    The tumor suppressor protein p16INK4a and its family members p15INK4b, p18INK4c and p19INK4d (the INK4 proteins) inhibit the cyclin-dependent kinases CDK4 and CDK6, which are key regulators of the retinoblastoma protein (pRb). pRb guards entry into the S phase of the mammalian cell division cycle (the cell cycle), a process evolved to ensure balanced cell proliferation. Deregulation of the cell cycle including the 'RB pathway' may have devastating consequences such as develo...

  13. Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages

    Directory of Open Access Journals (Sweden)

    Hirokazu Nakatsumi

    2017-11-01

    Full Text Available C-C chemokine ligand 2 (CCL2 plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF-κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1 as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB and that CCL2 produced by this pathway contributes to tumor progression.

  14. Recruitment Trends in Japan

    OpenAIRE

    Firkola, Peter

    2008-01-01

    This paper examines recent recruitment practices in large Japanese companies. It was found that many large companies have adapted recruitment practices in varying degrees to deal with the changing economic environment. These changes include increasing the number of hires, diversifying hiring conditions, extending the recruitment schedule, and dealing with labor turnover issues. The implications of these changes and the impact on companies and university students are then discussed.

  15. New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation.

    Science.gov (United States)

    Cassinat, B; Zassadowski, F; Ferry, C; Llopis, L; Bruck, N; Lainey, E; Duong, V; Cras, A; Despouy, G; Chourbagi, O; Beinse, G; Fenaux, P; Rochette Egly, C; Chomienne, C

    2011-04-01

    The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.

  16. Recruitment of general practices

    DEFF Research Database (Denmark)

    Riis, Allan; Jensen, Cathrine E; Maindal, Helle T

    2016-01-01

    -factors as determinants for successfully recruiting healthcare professionals: relationships, reputation, requirements, rewards, reciprocity, resolution, and respect. METHOD: This is a process evaluation of the seven R-factors. We applied these factors to guide the design of our recruitment strategy as well as to make...... adjustments when recruiting general practices in a guideline implementation study. In the guideline implementation study, we studied the effect of outreach visits, quality reports, and new patient stratification tools for low back pain patients. RESULTS: During a period of 15 months, we recruited 60 practices...

  17. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation

    DEFF Research Database (Denmark)

    Wu, Xudong; Johansen, Jens Vilstrup; Helin, Kristian

    2013-01-01

    Polycomb repressive complex 1 (PRC1) catalyzes lysine 119 monoubiquitylation on H2A (H2AK119ub1) and regulates pluripotency in embryonic stem cells (ESCs). However, the mechanisms controlling the binding of PRC1 to genomic sites and its catalytic activity are poorly understood. Here, we show that...... Fbxl10 interacts with Ring1B and Nspc1, forming a noncanonical PRC1 that is required for H2AK119ub1 in mouse ESCs. Genome-wide analyses reveal that Fbxl10 preferentially binds to CpG islands and colocalizes with Ring1B on Polycomb target genes. Notably, Fbxl10 depletion causes a decrease in Ring1B...... binding to target genes and a major loss of H2AK119ub1. Furthermore, genetic analyses demonstrate that Fbxl10 DNA binding capability and integration into PRC1 are required for H2AK119 ubiquitylation. ESCs lacking Fbxl10, like previously characterized Polycomb mutants, cannot differentiate properly...

  18. Recruiting and Retaining Cyberwarriors

    National Research Council Canada - National Science Library

    Westermeyer, Roger H

    2008-01-01

    .... Recruiting and retaining this highly skilled workforce is a significant challenge for the Air Force due to the high public and private sector demand for people with IT and related engineering skills...

  19. Electronic Recruitment at CERN

    CERN Multimedia

    2004-01-01

    The Human Resources Department switches to electronic recruitment. From now on whenever you are involved in a recruitment action you will receive an e-mail giving you access to a Web folder. Inside you will find a shortlist of applications drawn up by the Human Resources Department. This will allow you to consult the folder, at the same time as everyone else involved in the recruitment process, for the vacancy you are interested in. This new electronic recruitment system, known as e-RT, will be introduced in a presentation given at 10 a.m. on 11 February in the Main Auditorium. Implemented by AIS (Administrative Information Services) and the Human Resources Department, e-RT will cover vacancies open in all of CERN's recruitment programmes. The electronic application system was initially made available to technical students in July 2003. By December it was extended to summer students, fellows, associates and Local Staff. Geraldine Ballet from the Recruitment Service prefers e-RT to mountains of paper! The Hu...

  20. Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-α production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1.

    Science.gov (United States)

    Pedroza, Luis A; Kumar, Vipul; Sanborn, Keri B; Mace, Emily M; Niinikoski, Harri; Nadeau, Kari; Vasconcelos, Dewton de Moraes; Perez, Elena; Jyonouchi, Soma; Jyonouchi, Harumi; Banerjee, Pinaki P; Ruuskanen, Olli; Condino-Neto, Antonio; Orange, Jordan S

    2012-02-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity. To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of β-glucan through the Dectin-1 pathway, which is required for defense against Candida species. Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy. PBMCs from patients with APECED syndrome had reduced TNF-α responses after Dectin-1 ligation but in part used a Raf-1-mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-α release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain-containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane. AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  1. Single-molecule tracking in live Vibrio cholerae reveals that ToxR recruits the membrane-bound virulence regulator TcpP to the toxT promoter.

    Science.gov (United States)

    Haas, Beth L; Matson, Jyl S; DiRita, Victor J; Biteen, Julie S

    2015-04-01

    Vibrio cholerae causes the human disease cholera by producing a potent toxin. The V. cholerae virulence pathway involves an unusual transcription step: the bitopic inner-membrane proteins TcpP and ToxR activate toxT transcription. As ToxT is the primary direct transcription activator in V. cholerae pathogenicity, its regulation by membrane-localized activators is key in the disease process. However, the molecular mechanisms by which membrane-localized activators engage the transcription process have yet to be uncovered in live cells. Here we report the use of super-resolution microscopy, single-molecule tracking, and gene knockouts to examine the dynamics of individual TcpP proteins in live V. cholerae cells with < 40 nm spatial resolution on a 50 ms timescale. Single-molecule trajectory analysis reveals that TcpP diffusion is heterogeneous and can be described by three populations of TcpP motion: one fast, one slow, and one immobile. By comparing TcpP diffusion in wild-type V. cholerae to that in mutant strains lacking either toxR or the toxT promoter, we determine that TcpP mobility is greater in the presence of its interaction partners than in their absence. Our findings support a mechanism in which ToxR recruits TcpP to the toxT promoter for transcription activation. © 2014 John Wiley & Sons Ltd.

  2. Recruitment and Retention.

    Science.gov (United States)

    Combs, Jolene

    1986-01-01

    Suggests ways community college journalism instructors can recruit and retain students in journalism classes (e.g., host a high school press day, fund a journalism scholarship, sponsor events for high school journalism teachers and advisers, serve as counselor for journalism majors, have a yearly journalism convocation, and involve campus…

  3. Recruiting and Retaining Cyberwarriors

    Science.gov (United States)

    2008-02-07

    that are now entering the workforce. These Millennials , also referred to as Generation Y , the Echo Boomers, or the Internet Generation (Igen), were...38 NAS Insights, Generation Y : The Millennials , NAS Recruitment Communications, available from www.nasrecruitment.com/TalentTips/NASinsights...challenge is further exacerbated by a new generation , commonly referred to as Millennials , now coming into the workplace. The Millennials have

  4. [Recruitment in presbycusis].

    Science.gov (United States)

    Sánchez Legaza, E; Ciges Juan, M; González Pérez, M; Miranda Caravallo, J I

    2006-01-01

    Presbycusis is characterised by a sensorineural hearing loss, mainly in high frequencies, symmetrical and progressive and poor understanding. Recuritment, typical in cochlear hearing loss, would be present in cases of sensorial presbycusis which runs mainly in cochlear pathologies. We analyse variables and their possible interrelations with recruitment in 241 presbycusic patients.

  5. Sales Force Recruitment

    OpenAIRE

    Flaviu MEGHISAN

    2008-01-01

    The sales plan is put into practice through the tasks associated with sales plan implementation. Whereas sales plan formulation focuses on "doing the right things," implementation emphasizes "doing things right." The three major tasks involved in implementing a sales plan are (1) salesforce recruitment and selection, (2) salesforce training, and (3) salesforce motivation and compensation.

  6. 41 CFR 101-4.510 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... FEDERAL PROPERTY MANAGEMENT REGULATIONS GENERAL 4-NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION... recipient shall recruit members of the sex so discriminated against so as to overcome the effects of such... have the effect of discriminating on the basis of sex in violation of §§ 101-4.500 through 101-4.550. ...

  7. eHealth Recruitment Challenges

    Science.gov (United States)

    Thompson, Debbe; Canada, Ashanti; Bhatt, Riddhi; Davis, Jennifer; Plesko, Lisa; Baranowski, Tom; Cullen, Karen; Zakeri, Issa

    2006-01-01

    Little is known about effective eHealth recruitment methods. This paper presents recruitment challenges associated with enrolling African-American girls aged 8-10 years in an eHealth obesity prevention program, their effect on the recruitment plan, and potential implications for eHealth research. Although the initial recruitment strategy was…

  8. Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1-activated transcription of the interferon regulatory factor 1 gene (IRF1

    Directory of Open Access Journals (Sweden)

    Buro Lauren J

    2010-09-01

    Full Text Available Abstract Background Signal transducer and activator of transcription (STAT activation of gene expression is both rapid and transient, and when properly executed it affects growth, differentiation, homeostasis and the immune response, but when dysregulated it contributes to human disease. Transcriptional activation is regulated by alterations to the chromatin template. However, the role of histone modification at gene loci that are activated for transcription in response to STAT signaling is poorly defined. Results Using chromatin immunoprecipitation, we profiled several histone modifications during STAT1 activation of the interferon regulatory factor 1 gene (IRF1. Methylated lysine histone proteins H3K4me2, H3K4me3, H3K79me3, H3K36me3 and monoubiquitinated histone ubH2B are dynamic and correlate with interferon (IFNγ induction of STAT1 activity. Chemical inhibition of H3K4 methylation downregulates IRF1 transcription and decreases RNA polymerase II (Pol II occupancy at the IRF1 promoter. MEN1, a component of a complex proteins associated with Set1 (COMPASS-like complex and the hBRE1 component, RNF20, are localized to IRF1 in the uninduced state and are further recruited when IRF1 is activated. RNAi-mediated depletion of RNF20 lowers both ubH2B and H3K4me3, but surprisingly, upregulates IFNγ induced IRF1 transcription. The dynamics of phosphorylation in the C-terminal domain (CTD of Pol II are disrupted during gene activation as well. Conclusions H2B monoubiquitination promotes H3K4 methylation, but the E3 ubiquitin ligase, RNF20, is repressive of inducible transcription at the IRF1 gene locus, suggesting that ubH2B can, directly or indirectly, affect Pol II CTD phosphorylation cycling to exert control on ongoing transcription.

  9. c-Myb and GATA-3 cooperatively regulate IL-13 expression via conserved GATA-3 response element and recruit mixed lineage leukemia (MLL) for histone modification of the IL-13 locus.

    Science.gov (United States)

    Kozuka, Teruhiko; Sugita, Mayumi; Shetzline, Susan; Gewirtz, Alan M; Nakata, Yuji

    2011-12-01

    The c-Myb and GATA-3 transcription factors play important roles in T cell development. We recently reported that c-Myb, GATA-3, and Menin form a core transcription complex that regulates GATA-3 expression and ultimately Th2 cell development in human peripheral blood T cells. However, c-Myb roles for Th2 cytokine expression were not demonstrated. In this article, we report that c-Myb and GATA-3 cooperatively play an essential role in IL-13 expression though direct binding to a conserved GATA-3 response element (CGRE), an enhancer for IL-13 expression. c-Myb and GATA-3 were shown to activate the CGRE-IL-13 promoter by ∼160-fold, and mutation of the canonical Myb binding site completely abrogated CGRE enhancer activity. In contrast, mutation of the GATA binding site partially decreased CGRE enhancer activity. GATA-3 did not bind to CGRE when c-myb expression was silenced. c-Myb, GATA-3, Menin, and mixed lineage leukemia (MLL) bound to CGRE in human primary CD4(+) effector/memory cells. Moreover, c-myb silencing significantly decreased both methylation of histone H3K4 and acetylation of histone H3K9 at the IL-13 locus in CD4(+) effector/memory cells. Therefore, in addition to the strong enhancer effect for the transcription of IL-13, the c-Myb/GATA-3 complex recruits MLL to the CGRE for histone modification of the IL-13 locus during the differentiation of memory Th2 cells.

  10. 48 CFR 31.205-34 - Recruitment costs.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Recruitment costs. 31.205... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-34 Recruitment costs. (a) Subject to paragraph (b) of this subsection, the following costs are...

  11. Building an Effective Recruiting Funnel.

    Science.gov (United States)

    Sevier, Robert A.

    2000-01-01

    Focuses on the creation of an undergraduate recruiting funnel directed at traditional-age students. Most colleges have recruiting funnels, a series of contacts that move a prospective student from initial contact through the campus visit to matriculation. Discusses goals and strategies to include in the design of successful recruiting funnels.…

  12. Fast-Track Teacher Recruitment.

    Science.gov (United States)

    Grant, Franklin Dean

    2001-01-01

    Schools need a Renaissance human-resources director to implement strategic staffing and fast-track teacher-recruitment plans. The HR director must attend to customer satisfaction, candidate supply, web-based recruitment possibilities, stabilization of newly hired staff, retention of veteran staff, utilization of retired employees, and latest…

  13. Diversity employment and recruitment sources

    Energy Technology Data Exchange (ETDEWEB)

    1994-08-01

    Effective human resources management has been identified as one of four critical success factors in the Department of Energy Strategic Plan. The Plan states relative to this factor: ``The Department seeks greater alignment of resources with agency priorities and increased diversification of the workforce, including gender, ethnicity, age, and skills. This diversification will bring new thinking and perspectives that heretofore have not had a voice in departmental decision-making.`` This Guide has been developed as a key tool to assist Department of Energy management and administrative staff in achieving Goal 2 of this critical success factor, which is to ``Ensure a diverse and talented workforce.`` There are numerous sources from which to recruit minorities, women and persons with disabilities. Applying creativity and proactive effort, using traditional and non-traditional approaches, and reaching out to various professional, academic and social communities will increase the reservoir of qualified candidates from which to make selections. In addition, outreach initiatives will undoubtedly yield further benefits such as a richer cultural understanding and diversity awareness. The resource listings presented in this Guide are offered to encourage active participation in the diversity recruitment process. This Guide contains resource listings by state for organizations in the following categories: (1) African American Recruitment Sources; (2) Asian American/Pacific Islander Recruitment Sources; (3) Hispanic Recruitment Sources; (4) Native American/Alaskan Native Recruitment Sources; (5) Persons with Disabilities Recruitment Sources; and (6) Women Recruitment Sources.

  14. Recruitment Practices And Institutional Change

    DEFF Research Database (Denmark)

    Holm, Anna; Ulhøi, John Parm

    , and individuals’ social cognition. Among other things, this is reflected in the use of online recruitment and employer branding. The study concludes that the recruitment field has transformed and reviewed its practices due to institutional changes in how individuals search for employment and expect to be hired....

  15. Design of a cluster-randomized minority recruitment trial: RECRUIT.

    Science.gov (United States)

    Tilley, Barbara C; Mainous, Arch G; Smith, Daniel W; McKee, M Diane; Amorrortu, Rossybelle P; Alvidrez, Jennifer; Diaz, Vanessa; Ford, Marvella E; Fernandez, Maria E; Hauser, Robert A; Singer, Carlos; Landa, Veronica; Trevino, Aron; DeSantis, Stacia M; Zhang, Yefei; Daniels, Elvan; Tabor, Derrick; Vernon, Sally W

    2017-06-01

    Racial/ethnic minority groups remain underrepresented in clinical trials. Many strategies to increase minority recruitment focus on minority communities and emphasize common diseases such as hypertension. Scant literature focuses on minority recruitment to trials of less common conditions, often conducted in specialty clinics and dependent on physician referrals. We identified trust/mistrust of specialist physician investigators and institutions conducting medical research and consequent participant reluctance to participate in clinical trials as key-shared barriers across racial/ethnic groups. We developed a trust-based continuous quality improvement intervention to build trust between specialist physician investigators and community minority-serving physicians and ultimately potential trial participants. To avoid the inherent biases of non-randomized studies, we evaluated the intervention in the national Randomized Recruitment Intervention Trial (RECRUIT). This report presents the design of RECRUIT. Specialty clinic follow-up continues through April 2017. We hypothesized that specialist physician investigators and coordinators trained in the trust-based continuous quality improvement intervention would enroll a greater proportion of minority participants in their specialty clinics than specialist physician investigators in control specialty clinics. Specialty clinic was the unit of randomization. Using continuous quality improvement, the specialist physician investigators and coordinators tailored recruitment approaches to their specialty clinic characteristics and populations. Primary analyses were adjusted for clustering by specialty clinic within parent trial and matching covariates. RECRUIT was implemented in four multi-site clinical trials (parent trials) supported by three National Institutes of Health institutes and included 50 associated specialty clinics from these parent trials. Using current data, we have 88% power or greater to detect a 0.15 or

  16. 43 CFR 41.310 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Recruitment. 41.310 Section 41.310 Public... in Admission and Recruitment Prohibited § 41.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  17. 40 CFR 5.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Recruitment. 5.310 Section 5.310... in Admission and Recruitment Prohibited § 5.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  18. 28 CFR 54.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Recruitment. 54.310 Section 54.310... in Admission and Recruitment Prohibited § 54.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  19. 15 CFR 8a.310 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Recruitment. 8a.310 Section 8a.310... in Admission and Recruitment Prohibited § 8a.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  20. 6 CFR 17.310 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 6 Domestic Security 1 2010-01-01 2010-01-01 false Recruitment. 17.310 Section 17.310 Domestic... in Admission and Recruitment Prohibited § 17.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  1. 14 CFR 1253.310 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Recruitment. 1253.310 Section 1253.310... in Admission and Recruitment Prohibited § 1253.310 Recruitment. (a) Nondiscriminatory recruitment. A... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  2. 41 CFR 101-4.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Recruitment. 101-4.310... Admission and Recruitment Prohibited § 101-4.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient... recruitment and admission of students. A recipient may be required to undertake additional recruitment efforts...

  3. Human Resources Marketing and Recruiting: Essentials of Digital Recruiting

    CERN Document Server

    Purvis, James

    2016-01-01

    This chapter will cover digital recruitment from its definition thru to its history in recruitment and trends. The subject itself could cover an entire book or an entire module at university, so this chapter will broadly touch upon the key elements and considerations. Under cultural perspective, the recruitment life cycle will be broken down into its individual parts, and digital solutions will be examined for each individual part of the process together with the impact this has on the knowledge and challenges for the manager and team. The economic perspective will assist in prioritizing initiatives and building a business case for the introduction of digital recruiting solutions. The risk perspective will raise awareness of the potential pitfalls and the operational perspective on the key considerations for a successful implementation. Finally, the key messages of this chapter are summarized in the Do’s and Don’ts.

  4. Recruiting for Prior Service Market

    National Research Council Canada - National Science Library

    Thomas, Brian A; Givens, Eric

    2008-01-01

    ...) market based on data from: * DMDC (All services) * IRR (HRC-St. Louis) * AC/RC transition (HRC-Alexandria); 2) To recommend possible recruiting pools of applicants from the analyzed market data...

  5. 22 CFR 146.310 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Recruitment. 146.310 Section 146.310 Foreign... Recruitment Prohibited § 146.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 146.300 through 146.310 apply shall not discriminate on the basis of sex in the recruitment and admission...

  6. 49 CFR 25.310 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Recruitment. 25.310 Section 25.310 Transportation... Recruitment Prohibited § 25.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 25.300 through 25.310 apply shall not discriminate on the basis of sex in the recruitment and admission of...

  7. 45 CFR 86.23 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Recruitment. 86.23 Section 86.23 Public Welfare... in Admission and Recruitment Prohibited § 86.23 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which this subpart applies shall not discriminate on the basis of sex in the recruitment and...

  8. 10 CFR 1042.310 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Recruitment. 1042.310 Section 1042.310 Energy DEPARTMENT... Recruitment Prohibited § 1042.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 1042.300 through 1042.310 apply shall not discriminate on the basis of sex in the recruitment and admission...

  9. Spatial synchrony in cisco recruitment

    Science.gov (United States)

    Myers, Jared T.; Yule, Daniel L.; Jones, Michael L.; Ahrenstorff, Tyler D.; Hrabik, Thomas R.; Claramunt, Randall M.; Ebener, Mark P.; Berglund, Eric K.

    2015-01-01

    We examined the spatial scale of recruitment variability for disparate cisco (Coregonus artedi) populations in the Great Lakes (n = 8) and Minnesota inland lakes (n = 4). We found that the scale of synchrony was approximately 400 km when all available data were utilized; much greater than the 50-km scale suggested for freshwater fish populations in an earlier global analysis. The presence of recruitment synchrony between Great Lakes and inland lake cisco populations supports the hypothesis that synchronicity is driven by climate and not dispersal. We also found synchrony in larval densities among three Lake Superior populations separated by 25–275 km, which further supports the hypothesis that broad-scale climatic factors are the cause of spatial synchrony. Among several candidate climate variables measured during the period of larval cisco emergence, maximum wind speeds exhibited the most similar spatial scale of synchrony to that observed for cisco. Other factors, such as average water temperatures, exhibited synchrony on broader spatial scales, which suggests they could also be contributing to recruitment synchrony. Our results provide evidence that abiotic factors can induce synchronous patterns of recruitment for populations of cisco inhabiting waters across a broad geographic range, and show that broad-scale synchrony of recruitment can occur in freshwater fish populations as well as those from marine systems.

  10. Uncover the recruiter in you!

    CERN Multimedia

    2013-01-01

    2013 saw the launch of the one-day training course "Selecting the best person for CERN". So far, 10 courses have taken place and over 100 participants have taken part in this interactive, hands on experience.   The course has been met with much enthusiasm and positive feedback, with participants not only feeling better prepared and organised for the recruitment boards, but also equipped with concrete tools on how to prepare and conduct an effective selection interview. Following on from this success, further sessions are planned in 2014: we look forward to welcoming recruiting supervisors and board members who are likely to take part in a recruitment process, whether for LD or LD2IC, and who are interested in finding out more about how to get the most out of this important process! To enrol to this course, please follow this link: "Selecting the best person for CERN".

  11. Microvascular Recruitment in Insulin Resistance

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker

    the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...... hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...

  12. Microvascular Recruitment in Insulin Resistance

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker

    hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...... the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...

  13. Do recruitment ties affect wages?

    DEFF Research Database (Denmark)

    Larsen, Anna Folke; Rand, John; Torm, Nina Elisabeth

    This paper examines the extent to which recruitment ties affect individual wage outcomes in small and medium scale manufacturing firms. Based on a unique matched employer-employee dataset from Vietnam we find that there is a significant positive wage premium associated with obtaining a job through...... an informal contact, when controlling for standard determinants of wage compensation. Moreover, we show that the mechanism through which informal contacts affect wages depends on the type of recruitment tie used. The findings are robust across location, firm size categories and different worker types....

  14. Phytochemical regulation of the tumor suppressive microRNA, miR-34a, by p53-dependent and independent responses in human breast cancer cells.

    Science.gov (United States)

    Hargraves, Kris G; He, Lin; Firestone, Gary L

    2016-05-01

    The tumor suppressive microRNA miR-34a is transcriptionally regulated by p53 and shown to inhibit breast cancer cell proliferation as well as being a marker of increased disease free survival. Indole-3-carbinol (I3C) derived from cruciferous vegetables, artemisinin, extracted from the sweet wormwood plant, and artesunate, a semi-synthetic derivative of artemisinin, are phytochemicals with anti-tumorigenic properties however, little is known about the role of microRNAs in their mechanism of action. Human breast cancer cells expressing wild-type (MCF-7) or mutant p53 (T47D) were treated with a concentration range and time course of each phytochemical under conditions of cell cycle arrest as detected by flow cytometry to examine the potential connection between miR-34a expression and their anti-proliferative responses. Real-time PCR and western blot analysis of extracted RNA and total protein revealed artemsinin and artesunate increased miR-34a expression in a dose-dependent manner correlating with down-regulation of the miR-34a target gene, CDK4. I3C stimulation of miR-34a expression required functional p53, whereas, both artemisinin and artesunate up-regulated miR-34a expression regardless of p53 mutational status or in the presence of dominant negative p53. Phytochemical treatments inhibited the luciferase activity of a construct containing the wild-type 3'UTR of CDK4, but not those with a mutated miR-34a binding site, whereas, transfection of miR-34a inhibitors ablated the phytochemical mediated down-regulation of CDK4 and induction of cell cycle arrest. Our results suggest that miR-34a is an essential component of the anti-proliferative activities of I3C, artemisinin, and artesunate and demonstrate that both wild-type p53 dependent and independent pathways are responsible for miR-34a induction. © 2015 Wiley Periodicals, Inc.

  15. Wetland dynamics influence mid-continent duck recruitment

    Science.gov (United States)

    Anteau, Michael J.; Pearse, Aaron T.; Szymankski, Michael L.

    2013-01-01

    Recruitment is a key factor influencing duck population dynamics. Understanding what regulates recruitment of ducks is a prerequisite to informed habitat and harvest management. Quantity of May ponds (MP) has been linked to recruitment and population size (Kaminski and Gluesing 1987, Raveling and Heitmeyer 1989). However, wetland productivity (quality) is driven by inter-annual hydrological fluctuations. Periodic drying of wetlands due to wet-dry climate cycles releases nutrients and increases invertebrate populations when wet conditions return (Euliss et al. 1999). Wetlands may also become wet or dry within a breeding season. Accordingly, inter-annual and intra-seasonal hydrologic variation potentially influence duck recruitment. Here, we examined influences of wetland quantity, quality, and intra-seasonal dynamics on recruitment of ducks. We indexed duck recruitment by vulnerability-corrected age ratios (juveniles/adult females) for mid-continent Gadwall (Anas strepera). We chose Gadwall because the majority of the continental population breeds in the Prairie Pothole Region (PPR), where annual estimates of MP exist since 1974. We indexed wetland quality by calculating change in MP (?MP) over the past two years (?MP = 0.6[MPt – MPt-1] + 0.4[MPt – MPt-2]). We indexed intra-seasonal change in number of ponds by dividing the PPR mean standardized precipitation index for July by MP (hereafter summer index). MP and ?MP were positively correlated (r = 0.65); therefore, we calculated residual ?MP (?MPr) with a simple linear regression using MP, creating orthogonal variables. Finally, we conducted a multiple regression to examine how MP, ?MPr, and summer index explained variation in recruitment of Gadwall from 1976–2010. Our model explained 67% of the variation in mid-continent Gadwall recruitment and all three hydrologic indices were positively correlated with recruitment (Figure 1). Type II semi-partial R2 estimates indicated that MP accounted for 41%, ?MPr

  16. Recruiters, Advertising, and Navy Enlistments,

    Science.gov (United States)

    1979-10-01

    standards and perhaps recruiters’ efforts. Another factor that has a sizable effect is unemployment. A one- point increase in the youth unemployment rate...one-percentage-point increase in the youth unemployment rate would yield 1,717 HSGs and 1,258 (73 percent) would be in the upper mental groups. The

  17. A Blueprint for Student Recruitment

    Science.gov (United States)

    Chamberlain, Frank M.

    1977-01-01

    A marketing plan from the Young Presidents' Organization Task Force is offered: define the market; identify the target student; clarify the college selection process; assess the competition; define the college in terms of market needs; develop a recruiting strategy; develop objectives for the year; spell out the tactics; and manage for results.…

  18. Generational Recruiting: Applying Generational Theory to Tactical Level Recruiting

    Science.gov (United States)

    2013-04-24

    recruiters regarding the influences, traits, values, and communications methods best suited for Millenials ’ influencers. The section now examines the...between work and family; with respect to authority Millenials desire performance feedback; Millenials are "wired" to the internet and are considered...technological experts. With regard to values, RVS polling found that Millenials top four values are family security, health, freedom, and true

  19. International Student Recruitment: Trends and Challenges

    Science.gov (United States)

    Falcone, Santa

    2017-01-01

    This paper provides a review of current trends in international student recruitment. Focusing specifically on recruitment of Chinese students, important aspects of China's educational system relevant to recruitment are presented. Barriers to Chinese student recruitment are then discussed. Successful, employed, international graduates validate…

  20. 20 CFR 655.30 - Supervised recruitment.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Supervised recruitment. 655.30 Section 655.30... Workers) § 655.30 Supervised recruitment. (a) Supervised recruitment. Where an employer is found to have... failed to adequately conduct recruitment activities or failed in any obligation of this part, the CO may...

  1. 44 CFR 19.310 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Recruitment. 19.310 Section... RECEIVING FEDERAL FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 19.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 19.300 through 19...

  2. 45 CFR 618.310 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Recruitment. 618.310 Section 618.310 Public... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 618.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 618.300 through 618.310 apply shall not discriminate on the...

  3. 24 CFR 3.310 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Recruitment. 3.310 Section 3.310... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 3.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 3.300 through 3.310 apply shall not discriminate on the basis...

  4. 10 CFR 5.310 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Recruitment. 5.310 Section 5.310 Energy NUCLEAR REGULATORY... FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 5.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 5.300 through 5.310 apply shall not...

  5. 29 CFR 36.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Recruitment. 36.310 Section 36.310 Labor Office of the... FEDERAL FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 36.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 36.300 through 36.310...

  6. 36 CFR 1211.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Recruitment. 1211.310 Section... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 1211.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 1211.300 through 1211.310 apply shall not discriminate on the...

  7. 38 CFR 23.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Recruitment. 23.310... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 23.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 23.300 through 23.310 apply shall not discriminate on the...

  8. 45 CFR 83.12 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Recruitment. 83.12 Section 83.12 Public Welfare... § 83.12 Recruitment. (a) Comparable recruitment. A federally supported entity shall, with respect to... demonstrate that such action is part of a recruitment program which does not have the effect of discriminating...

  9. 7 CFR 15a.53 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Recruitment. 15a.53 Section 15a.53 Agriculture Office... Activities Prohibited § 15a.53 Recruitment. (a) Nondiscriminatory recruitment and hiring. A recipient shall not discriminate on the basis of sex in the recruitment and hiring of employees. Where a recipient has...

  10. 32 CFR 196.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Recruitment. 196.310 Section 196.310 National... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 196.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 196.300 through 196.310 apply shall not discriminate on the...

  11. 20 CFR 656.21 - Supervised recruitment.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Supervised recruitment. 656.21 Section 656.21... Supervised recruitment. (a) Supervised recruitment. Where the Certifying Officer determines it appropriate, post-filing supervised recruitment may be required of the employer for the pending application or...

  12. 18 CFR 1317.310 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Recruitment. 1317.310... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 1317.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 1317.300 through 1317.310 apply shall not discriminate on the...

  13. 31 CFR 28.310 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Recruitment. 28.310 Section 28.310... Basis of Sex in Admission and Recruitment Prohibited § 28.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 28.300 through 28.310 apply shall not discriminate on the basis of sex in...

  14. 45 CFR 2555.310 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Recruitment. 2555.310 Section 2555.310 Public... Discrimination on the Basis of Sex in Admission and Recruitment Prohibited § 2555.310 Recruitment. (a) Nondiscriminatory recruitment. A recipient to which §§ 2555.300 through 2555.310 apply shall not discriminate on the...

  15. Diverse models for the prediction of CDK4 inhibitory activity of ...

    Indian Academy of Sciences (India)

    employed as the independent variables to perform a linear regression, the method is termed as PCR.73. In the present study, the dataset was divided into training and test set by random selection method for. MLR, PLSR and PCR methods using pIC50 [pIC50 = −log(IC50 ∗ 10−6) as dependent variable and vari-.

  16. E-recruitment and Selection

    DEFF Research Database (Denmark)

    Holm, Anna B.; Haahr, Lars

    2018-01-01

    The use of information and communication technologies has revolutionized e-recruitment and selection function in many organizations, especially transforming it into a time- and space-independent process of sourcing and evaluating candidates. In the process, organizations rely on websites, social...... media and job portals for sourcing candidates and deploy computerized and online assessment tools when selecting the best-qualified applicants. Similarly, their communication with jobseekers has moved to cyberspace and is often performed through applicant tracking systems, where hiring managers use...... mobile technologies to track and evaluate candidates. In this chapter, we present an overview of e-recruitment and selection practices and discuss the use of technology throughout the hiring process....

  17. Hezbollah: The Dynamics of Recruitment

    Science.gov (United States)

    2011-05-19

    the application of the age structure percentage 130 Jane’s World Insurgency and Terrorism database, Hizbullah (Mar 25, 2011) http://jwit.janes.com...The age structure percentage is 67.1%, which now reduces the Shiite population number to approximately 1,417,000 – the number of young as well as...middle aged Shiites potentially available for recruitment.134 The final calculation is the application of the male percentage for the age structure of

  18. A role for cargo in Arf-dependent adaptor recruitment.

    Science.gov (United States)

    Caster, Amanda H; Sztul, Elizabeth; Kahn, Richard A

    2013-05-24

    Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers. Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers. The recruitment of the adaptors is mediated by activated Arf GTPases, and the Arf-adaptor complexes mark sites of carrier formation. However, the nature of the signal(s) that initiates carrier biogenesis remains unknown. We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR), and M6PR lacking a C-terminal domain M6PRΔC). We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event. Cargos do not promote adaptor recruitment to all compartments in which they reside, and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment. We document that within a given compartment different cargos recruit different adaptors, suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor. Using temperature block, brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles. These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic.

  19. A Role for Cargo in Arf-dependent Adaptor Recruitment*

    Science.gov (United States)

    Caster, Amanda H.; Sztul, Elizabeth; Kahn, Richard A.

    2013-01-01

    Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers. Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers. The recruitment of the adaptors is mediated by activated Arf GTPases, and the Arf-adaptor complexes mark sites of carrier formation. However, the nature of the signal(s) that initiates carrier biogenesis remains unknown. We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR), and M6PR lacking a C-terminal domain M6PRΔC). We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event. Cargos do not promote adaptor recruitment to all compartments in which they reside, and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment. We document that within a given compartment different cargos recruit different adaptors, suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor. Using temperature block, brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles. These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic. PMID:23572528

  20. Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27Kip1 into cyclin E/CDK2 complexes.

    Science.gov (United States)

    Cheney, I W; Neuteboom, S T; Vaillancourt, M T; Ramachandra, M; Bookstein, R

    1999-05-15

    Genetic alterations in the MMAC1 tumor suppressor gene (also referred to as PTEN or TEP1) occur in several types of human cancers including glioblastoma. Growth suppression induced by overexpression of MMAC1 in cells with mutant MMAC1 alleles is thought to be mediated by the inhibition of signaling through the phosphatidylinositol 3-kinase pathway. However, the exact biochemical mechanisms by which MMAC1 exerts its growth-inhibitory effects are still unknown. Here we report that recombinant adenovirus-mediated overexpression of MMAC1 in three different MMAC1-mutant glioblastoma cell lines blocked progression from G0/G1 to S phase of the cell cycle. Cell cycle arrest correlated with the recruitment of the cyclin-dependent kinase (CDK) inhibitor, p27Kip1, to cyclin E immunocomplexes, which resulted in a reduction in CDK2 kinase activities and a decrease in levels of endogenous phosphorylated retinoblastoma protein. CDK4 kinase activities were unaffected, as were the levels of the CDK inhibitor p21Cip1 present in cyclin E immunocomplexes. Therefore, overexpression of MMAC1 via adenovirus-mediated gene transfer suppresses tumor cell growth through cell cycle inhibitory mechanisms, and as such, represents a potential therapeutic approach to treating glioblastomas.

  1. Recruitment dynamics in adaptive social networks

    International Nuclear Information System (INIS)

    Shkarayev, Maxim S; Shaw, Leah B; Schwartz, Ira B

    2013-01-01

    We model recruitment in adaptive social networks in the presence of birth and death processes. Recruitment is characterized by nodes changing their status to that of the recruiting class as a result of contact with recruiting nodes. Only a susceptible subset of nodes can be recruited. The recruiting individuals may adapt their connections in order to improve recruitment capabilities, thus changing the network structure adaptively. We derive a mean-field theory to predict the dependence of the growth threshold of the recruiting class on the adaptation parameter. Furthermore, we investigate the effect of adaptation on the recruitment level, as well as on network topology. The theoretical predictions are compared with direct simulations of the full system. We identify two parameter regimes with qualitatively different bifurcation diagrams depending on whether nodes become susceptible frequently (multiple times in their lifetime) or rarely (much less than once per lifetime). (paper)

  2. Gender bias in academic recruitment

    DEFF Research Database (Denmark)

    Abramo, Giovanni; D’Angelo, Ciriaco Andrea; Rosati, Francesco

    2016-01-01

    It is well known that women are underrepresented in the academic systems of many countries. Gender discrimination is one of the factors that could contribute to this phenomenon. This study considers a recent national academic recruitment campaign in Italy, examining whether women are subject...... to more or less bias than men. The findings show that no gender-related differences occur among the candidates who benefit from positive bias, while among those candidates affected by negative bias, the incidence of women is lower than that of men. Among the factors that determine success in a competition...

  3. U.S. Army Recruiter Allocation Model

    National Research Council Canada - National Science Library

    Brence, John

    2004-01-01

    .... Our methodology will build on both the new and old schools of recruiting by conducting stakeholder interviews that will lead us to a model that is an efficient starting point for the Recruiter Mission Allocation (RMA...

  4. Corporate Recruiters Survey: 2014 Survey Report

    Science.gov (United States)

    Estrada Worthington, Rebecca

    2014-01-01

    The 2014 Corporate Recruiters Survey Report examines the current hiring outlook for graduate business students and analyzes demand by industry and world region, salaries, job functions, and mobility in regional job placement. It also explores recruiter behavior, including recruitment practices and school and candidate selection criteria, and…

  5. 28 CFR 345.31 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Recruitment. 345.31 Section 345.31 Judicial Administration FEDERAL PRISON INDUSTRIES, INC., DEPARTMENT OF JUSTICE FEDERAL PRISON INDUSTRIES (FPI) INMATE WORK PROGRAMS Recruitment and Hiring Practices § 345.31 Recruitment. Inmate workers for...

  6. Faculty Recruitment in an Era of Change

    Science.gov (United States)

    Levine, Marilyn; Schimpf, Martin

    2010-01-01

    Faculty recruitment is a challenge for administration and departments, especially in an era of change in the academy. This article builds on information from an interactive conference panel session that focused on faculty recruitment best practices. The article addresses faculty recruitment strategies that focus on the optimization of search…

  7. Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes

    OpenAIRE

    Bache, Kristi G.; Brech, Andreas; Mehlum, Anja; Stenmark, Harald

    2003-01-01

    Hrs and the endosomal sorting complexes required for transport, ESCRT-I, -II, and -III, are involved in the endosomal sorting of membrane proteins into multivesicular bodies and lysosomes or vacuoles. The ESCRT complexes are also required for formation of intraluminal endosomal vesicles and for budding of certain enveloped RNA viruses such as HIV. Here, we show that Hrs binds to the ESCRT-I subunit Tsg101 via a PSAP motif that is conserved in Tsg101-binding viral proteins. Depletion of Hrs ca...

  8. Soy milk digestion extract inhibits progression of prostate cancer cell growth via regulation of prostate cancer‑specific antigen and cell cycle-regulatory genes in human LNCaP cancer cells.

    Science.gov (United States)

    Kang, Nam-Hee; Shin, Hee-Chang; Oh, Seunghyun; Lee, Kyun-Hee; Lee, Yoon-Bok; Choi, Kyung-Chul

    2016-08-01

    Soy milk, which is produced from whole soybeans, contains a variety of biologically active components. Isoflavones are a class of soy-derived phytoestrogens with beneficial effects, among which genistein (GEN) has been previously indicated to reduce the risk of prostate cancer. The present study evaluated the effects of soy milk digestion extract (SMD) on the progression of prostate cancer via the estrogen receptor (ER)β in human LNCaP prostate cancer cells. To evaluate the effects of SMD (daizein, 1.988 mg/100g, glycitein, 23.537 mg/100 g and GEN, 0.685 mg/100g) on cell proliferation, LNCaP cells were cultured in media containing vehicle (0.1% dimethyl sulfoxide), 17β‑estradiol (E2; 2.7x10‑7 mg/ml), GEN (2.7x10-2 mg/ml) of SMD (total aglycon concentration, 0.79 mg/ml), after which the cell viability was examined using an MTT assay. The cell viability was significantly elevated by E2 (by 45±0.18%), while it was markedly reduced by GEN (73.2±0.03%) or SMD (74.8±0.09%). Semi‑quantitative reverse transcription polymerase chain reaction analysis was performed to assess the mRNA expression levels of target genes, including ERβ, prostate cancer‑specific antigen (PSA) and cell cycle regulators p21, Cyclin D1 and cyclin-dependent kinase (CDK)4. The expression of ERβ was almost completely diminished by E2, whereas it was significantly elevated by SMD. In addition, the expression levels of PSA were considerably reduced by SMD. The expression of p21 was significantly elevated by SMD, while it was markedly reduced by E2. Of note, the expression levels of Cyclin D1 and CDK4 were considerably elevated by E2, while being significantly reduced by GEN and SMD. All of these results indicated that SMD may inhibit the proliferation of human prostate cancer cells via regulating the expression of ERβ, PSA, p21, Cyclin D1 and CDK4 in an ER-dependent manner.

  9. When is normative recruitment legitimate?

    Directory of Open Access Journals (Sweden)

    Lars Øystein Ursin

    2008-11-01

    Full Text Available Rosamond Rhodes and John Harris have both recently argued that we all have a general moral duty to participate in medical research. However, neither Rhodes' nor Harris' arguments in support of this obligation stand up to scrutiny, and severe and convincing criticism has been levelled against their case. Still, to refute their arguments is not to refute the conclusion. There seems to be some truth in the view that when people are asked to take part in medical research, their choice is not completely morally neutral. In this article, we argue that the proper question to ask is when, rather than if, a certain moral duty to volunteer for medical research can be appealed to. To answer this question, we need a denser description of relevant research projects and their context rather than just describing medical research in general. Drawing on our study of participants in the Norwegian HUNT biobank, we use the normative implications of the Norwegian concept «dugnad» as an analogy to discuss the requirement of providing neutral information to potential biobank participants in order to promote their free and informed decision as to whether or not to take part. We suggest that normative recruitment is not just a question of principles and ethics. It is also a question of research design and the creation of the common good in the community where the research takes place.http://dx.doi.org/10.5324/eip.v2i2.1697

  10. Recruitment to the Norwegian fishing fleet: storylines, paradoxes, and pragmatism in Norwegian fisheries and recruitment policy

    OpenAIRE

    Sønvisen, Signe Annie

    2013-01-01

    The majority of actors in the Norwegian fisheries consider recruitment of fishers to be the main future challenge for the Norwegian fishing fleet. As fleet recruitment is a highly politicized field, the problem of how to mitigate the recruitment problem is a subject of heavy debate. Some argue that recruitment problems are caused by low fleet profitability, while others argue that recruitment problems are caused by fleet restructuring polices. This article aims to explore th...

  11. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

    Directory of Open Access Journals (Sweden)

    Yuping Luo

    2010-04-01

    Full Text Available Fragile X syndrome (FXS, the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP. FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs. We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.

  12. Cyclin D3 interacts with vitamin D receptor and regulates its transcription activity

    International Nuclear Information System (INIS)

    Jian Yongzhi; Yan Jun; Wang Hanzhou; Chen Chen; Sun Maoyun; Jiang Jianhai; Lu Jieqiong; Yang Yanzhong; Gu Jianxin

    2005-01-01

    D-type cyclins are essential for the progression through the G1 phase of the cell cycle. Besides serving as cell cycle regulators, D-type cyclins were recently reported to have transcription regulation functions. Here, we report that cyclin D3 is a new interacting partner of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors for steroid hormones, thyroid hormone, and the fat-soluble vitamins A and D. The interaction was confirmed with methods of yeast two-hybrid system, in vitro binding analysis and in vivo co-immunoprecipitation. Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction. Confocal microscopy analysis showed that ligand-activated VDR led to an accumulation of cyclin D3 in the nuclear region. Cyclin D3 up-regulated transcriptional activity of VDR and this effect was counteracted by overexpression of CDK4 and CDK6. These findings provide us a new clue to understand the transcription regulation functions of D-type cyclins

  13. Understanding Millennials to Improve Recruiting Efficiency

    Science.gov (United States)

    2011-03-24

    efficient recruiting of Millennials . There is not a consistently strong linkage within the command to explain national advertising messaging methodology to...St ra te gy R es ea rc h Pr oj ec t UNDERSTANDING MILLENNIALS TO IMPROVE RECRUITING EFFICIENCY BY LIEUTENANT COLONEL HEATHER GARRETT...Research Project 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Understanding Millennials to Improve Recruiting Efficiency 5a

  14. Recruitment to the All Volunteer Force

    National Research Council Canada - National Science Library

    Harries-Jenkins, Gwyn

    2001-01-01

    Western military establishments which have decided to shift from conscription (the draft) to volunteerism as the basis of recruitment to their armed forces, commonly face very considerable challenges...

  15. Recruiting Diverse Smokers: Enrollment Yields and Cost

    Directory of Open Access Journals (Sweden)

    Kaitlyn E. Brodar

    2016-12-01

    Full Text Available To help tobacco control research better include vulnerable populations, we sought to identify effective ways to recruit diverse smokers. In 2014–2015, we recruited 2149 adult cigarette smokers in California and North Carolina, United States, to participate in a randomized trial of pictorial cigarette pack warnings. The most effective means of recruiting smokers were the classified advertising website Craigslist (28% of participants, word of mouth (23%, Facebook (16%, and flyers or postcards (14%. Low-income and African American smokers were more likely to respond to interpersonal contact (including staff in-person recruitment and word of mouth than were high-income and non-African American smokers (all p < 0.05. Hispanic and gay, lesbian, and bisexual smokers were more likely to be recruited by Craigslist than non-Hispanic and straight smokers (both p < 0.05. Of the recruitment methods requiring cost, the cheapest was Craigslist ($3–7 per smoker. The most expensive methods were newspaper ads in California ($375 per smoker and staff in-person recruiting in North Carolina ($180 per smoker. Successfully recruiting diverse smokers requires using multiple methods including interpersonal, online, and other media. Craigslist and word of mouth are especially useful and low-cost ways to recruit diverse smokers.

  16. Recruiting Diverse Smokers: Enrollment Yields and Cost.

    Science.gov (United States)

    Brodar, Kaitlyn E; Hall, Marissa G; Butler, Eboneé N; Parada, Humberto; Stein-Seroussi, Al; Hanley, Sean; Brewer, Noel T

    2016-12-16

    To help tobacco control research better include vulnerable populations, we sought to identify effective ways to recruit diverse smokers. In 2014-2015, we recruited 2149 adult cigarette smokers in California and North Carolina, United States, to participate in a randomized trial of pictorial cigarette pack warnings. The most effective means of recruiting smokers were the classified advertising website Craigslist (28% of participants), word of mouth (23%), Facebook (16%), and flyers or postcards (14%). Low-income and African American smokers were more likely to respond to interpersonal contact (including staff in-person recruitment and word of mouth) than were high-income and non-African American smokers (all p < 0.05). Hispanic and gay, lesbian, and bisexual smokers were more likely to be recruited by Craigslist than non-Hispanic and straight smokers (both p < 0.05). Of the recruitment methods requiring cost, the cheapest was Craigslist ($3-7 per smoker). The most expensive methods were newspaper ads in California ($375 per smoker) and staff in-person recruiting in North Carolina ($180 per smoker). Successfully recruiting diverse smokers requires using multiple methods including interpersonal, online, and other media. Craigslist and word of mouth are especially useful and low-cost ways to recruit diverse smokers.

  17. 22 CFR 229.310 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... Relations AGENCY FOR INTERNATIONAL DEVELOPMENT NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS... admission of students. A recipient may be required to undertake additional recruitment efforts for one sex... action pursuant to § 229.110(b). (b) Recruitment at certain institutions. A recipient to which §§ 229.300...

  18. Minority Teacher Recruitment and Retention Strategies

    Science.gov (United States)

    Kearney-Gissendaner, Janet E.

    2010-01-01

    The tools and resources in this book help school leaders seamlessly incorporate minority teacher recruitment and retention programs into current human-resources activities. With details about exemplary minority teacher recruitment and retention programs, this book also showcases strategies for how to replicate such programs in your own school or…

  19. Implementation of Staff Recruitment Policies and Diversity ...

    African Journals Online (AJOL)

    This paper reports on the findings of a study that delved into these reasons, with specific reference to staff recruitment policies and their implementation. It reports that the fairness of the universities' employee recruitment guidelines and the way these are implemented are significantly and positively with the universities' ...

  20. Recruiting leaders: an analysis of leadership advertisements

    NARCIS (Netherlands)

    den Hartog, D.N.; Caley, A.; Dewe, P.

    2007-01-01

    Recruiting the right leaders is an important challenge for organisations. How do organisations find these leaders? This article looks at the recruitment of leaders through advertisements. We address to what extent the 'vocabulary of leadership' originating in influential leadership theories is

  1. Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

    Science.gov (United States)

    Mohamed, Tamer M A; Ang, Yen-Sin; Radzinsky, Ethan; Zhou, Ping; Huang, Yu; Elfenbein, Arye; Foley, Amy; Magnitsky, Sergey; Srivastava, Deepak

    2018-03-22

    Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-β and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Analysis of Recruit Attrition from the Navy's Delayed Entry Program and Recruit Training Command

    National Research Council Canada - National Science Library

    Neuhalfen, Jon K

    2007-01-01

    .... The analysis uses the PRIDE database, provided by Commander, Navy Recruiting Command. Trend analyses are used to identify significant changes in enlistment and attrition behavior for recruits who joined from fiscal years 1998 through 2005...

  3. Allocation of Recruiting Resources Across Navy Recruiting Stations and Metropolitan Areas

    National Research Council Canada - National Science Library

    Jarosz, Suzanne

    1999-01-01

    .... However, the allocation of these resources across the 31 Navy recruiting districts must be made based on the characteristics of each district, and recruiters must be placed in geographic locations...

  4. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

    DEFF Research Database (Denmark)

    Goettsch, Claudia; Hutscheson, JD; Aikawa, M

    2016-01-01

    Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain...... obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin...... regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2-dependent C-terminal phosphorylation...

  5. Biotic interactions at hydrothermal vents: Recruitment inhibition by the mussel Bathymodiolus thermophilus

    Science.gov (United States)

    Lenihan, H. S.; Mills, S. W.; Mullineaux, L. S.; Peterson, C. H.; Fisher, C. R.; Micheli, F.

    2008-12-01

    The structure and dynamics of marine communities are regulated in part by variation in recruitment. As in other ecosystems, recruitment at deep-sea hydrothermal vents is controlled by the interplay of propagule supply and behavior, gradients in physical-chemical conditions, and biotic interactions during pre- and post-settlement periods. Recent research along the East Pacific Rise indicates that inhibition of recently settled larvae by mobile predators (mainly limpets) influences patterns of recruitment and subsequent community succession. We conducted a manipulative experiment at the same sites (˜2510 m water depth) to test whether high-density assemblages of the mussel Bathymodiolus thermophilus also inhibit recruitment. In a preliminary study, recruitment of vent invertebrates within the faunal zone dominated by B. thermophilus was strikingly different at two sites, East Wall and Worm Hole. East Wall had high densities of mussels but very low total recruitment. In contrast, Worm Hole had few mussels but high recruitment. Using the submersible Alvin, we transplanted a large number of mussels from East Wall to Worm Hole and quantified recruitment on basalt blocks placed in three treatments: (1) naturally high densities of mussels at East Wall; (2) naturally low densities of mussels at Worm Hole; and (3) high densities of transplanted mussels at Worm Hole. After 11 months, a total of 24 taxa had recruited to the basalt blocks. Recruitment was 44-60% lower in the transplanted high-density mussel patch at Worm Hole and the natural high-density patch at East Wall than within the natural low-density patch at Worm Hole. Biotic processes that may have caused the pattern of recruitment observed included predation of larvae via water filtration by mussels, larval avoidance of superior competitors, interference competition, and enhanced predation by species within the mussel-bed community. Our results indicate that biotic interactions affecting recruitment must be

  6. Function of cell-cycle regulators in predicting silent pituitary adenoma progression following surgical resection.

    Science.gov (United States)

    Park, Sung Hyun; Jang, Ji Hwan; Lee, Young Min; Kim, Joon Soo; Kim, Kyu Hong; Kim, Young Zoon

    2017-12-01

    The present study investigated the use of cell-cycle regulators for predicting the progression of silent pituitary adenoma (SPA) following surgical resection, via immunohistochemical analysis of tumor samples obtained by surgical resection. The medical records of patients diagnosed with SPA between January 2000 and December 2013 in the Samsung Changwon Hospital, Sungkyunkwan University School of Medicine (Changwon, South Korea) were reviewed. Immunohistochemical staining was performed on sections of the archived, paraffin-embedded tissues obtained by surgery, with all tissues stained for cell-cycle regulatory proteins p16, p15, p21, cyclin-dependent kinase (CDK)4, CDK6, retinoblastoma protein (pRb) and cyclin D1, as well as E3 ubiquitin-protein ligase mib1 (MIB-1) antigen and p53. The primary end-point was to investigate the expression of cell-cycle regulatory proteins in SPA. The secondary end-point was to estimate the progression-free survival of patients with SPA following surgical resection and to identify its association with the expression of cell-cycle regulatory proteins. Of the 127 SPA samples, 44 (34.6%) were from patients with progression during a mean follow-up period of 62.4 months (range, 24.2-118.9 months). Immunohistochemical overexpression was identified in 61 samples (48.0%) for p16, 38 samples (29.9%) for p15, 19 samples (15.0%) for p21, 49 samples (38.6%) for CDK4, 17 samples (13.4%) for CDK6, 57 samples (44.9%) for pRb and in 65 samples (51.2%) for cyclin D1. Multivariate analysis revealed that null cell adenoma [95% confidence interval (CI), 0.276-0.808], somatotroph SPAs (95% CI, 1.296-3.121), corticotroph SPAs (95% CI, 1.811-4.078), pluripotent SPAs (95% CI, 2.264-5.194), decreased expression of p16 (95% CI, 2.724-5.588), overexpression of pRb (95% CI, 2.557-5.333), cyclin D1 (95% CI, 1.894-4.122) and MIB-1 (95% CI, 1.561-4.133), increased mitotic index (95% CI, 1.228-4.079), increased p53 expression (95% CI, 1.307-4.065) and invasion into

  7. Childhood poverty and recruitment of adult emotion regulatory neurocircuitry

    Science.gov (United States)

    Ma, Sean T.; Okada, Go; Shaun Ho, S.; Swain, James E.; Evans, Gary W.

    2015-01-01

    One in five American children grows up in poverty. Childhood poverty has far-reaching adverse impacts on cognitive, social and emotional development. Altered development of neurocircuits, subserving emotion regulation, is one possible pathway for childhood poverty’s ill effects. Children exposed to poverty were followed into young adulthood and then studied using functional brain imaging with an implicit emotion regulation task focused. Implicit emotion regulation involved attention shifting and appraisal components. Early poverty reduced left dorsolateral prefrontal cortex recruitment in the context of emotional regulation. Furthermore, this emotion regulation associated brain activation mediated the effects of poverty on adult task performance. Moreover, childhood poverty also predicted enhanced insula and reduced hippocampal activation, following exposure to acute stress. These results demonstrate that childhood poverty can alter adult emotion regulation neurocircuitry, revealing specific brain mechanisms that may underlie long-term effects of social inequalities on health. The role of poverty-related emotion regulatory neurocircuitry appears to be particularly salient during stressful conditions. PMID:25939653

  8. Childhood poverty and recruitment of adult emotion regulatory neurocircuitry.

    Science.gov (United States)

    Liberzon, Israel; Ma, Sean T; Okada, Go; Ho, S Shaun; Swain, James E; Evans, Gary W

    2015-11-01

    One in five American children grows up in poverty. Childhood poverty has far-reaching adverse impacts on cognitive, social and emotional development. Altered development of neurocircuits, subserving emotion regulation, is one possible pathway for childhood poverty's ill effects. Children exposed to poverty were followed into young adulthood and then studied using functional brain imaging with an implicit emotion regulation task focused. Implicit emotion regulation involved attention shifting and appraisal components. Early poverty reduced left dorsolateral prefrontal cortex recruitment in the context of emotional regulation. Furthermore, this emotion regulation associated brain activation mediated the effects of poverty on adult task performance. Moreover, childhood poverty also predicted enhanced insula and reduced hippocampal activation, following exposure to acute stress. These results demonstrate that childhood poverty can alter adult emotion regulation neurocircuitry, revealing specific brain mechanisms that may underlie long-term effects of social inequalities on health. The role of poverty-related emotion regulatory neurocircuitry appears to be particularly salient during stressful conditions. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  9. Regulation of apoptosis and cell cycle in irradiated mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Won Yong; Song, Mi Hee; Hung, Eun Ji; Seong, Jin Sil; Suh, Chang Ok [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)

    2001-06-01

    To investigate the regulation of apoptosis and cell cycle in mouse brain irradiation. 8-week old male mice, C57B 1/6J were given whole body {gamma} -radiation with a single dose of 25 Gy using Cobalt 60 irradiator. At different times 1, 2, 4, 8 and 24hr after irradiation, mice were killed and brain tissues were collected. Apoptotic cells were scored by TUNEL assay. Expression of p53, Bcl-2, and Bax and cell cycle regulating molecules; cyclins BI, D1, E and cdk2, cdk4, p34{sup cdc2} were analysed by Western blotting. Cell cycle was analysed by flow cytometry. The peak of radiation induced apoptosis is shown at 8 hour after radiation. With a single 25 Gy irradiation, the peak of apoptotic index in C57B1/6J is 24.0{+-}0.25 (p<0.05) at 8 hour after radiation. Radiation upregulated the expression of p53/tubulin, Bax/tubulin, and Bcl-2/tubulin with 1.3, 1.1 and 1.45 fold increase, respectively were shown at the peak level at 8 hour after radiation. The levels of cell cycle regulating molecules after radiation are not changed significantly except cyclin D1 with 1.3 fold increase. Fractions of Go-G 1, G2-M and S phase in the cell cycle does not specific changes by time. In mouse brain tissue, radiation induced apoptosis is particularly shown in a specific area, subependyma. These results and lack of radiation induced changes in cell cycle offer better understanding of radiation response of normal brain tissue.

  10. The complexity of arterial classical monocyte recruitment

    NARCIS (Netherlands)

    Drechsler, Maik; Soehnlein, Oliver

    2013-01-01

    Accumulation of classical monocytes is imperative for the progression of atherosclerosis. Hence, therapeutic interference with mechanisms of lesional monocyte recruitment, the primary mechanism controlling macrophage accumulation, may allow for targeting atheroprogression and its clinical

  11. The Canadian Forces Recruitment/Attrition Model

    National Research Council Canada - National Science Library

    Wait, Tracey

    1998-01-01

    ...), as part of its mandate to provide analysis of potential impacts of trends and change on defense and defense related issues, has designed a prototype model of recruitment and attrition of the Canadian Forces (C F...

  12. Tackling the nursing shortage: recruitment or retention?

    Science.gov (United States)

    2017-04-05

    Becoming a nurse used to be pretty straightforward. The vast majority of potential recruits applied to their local nursing school, learned on the job, qualified after three years and started work straightaway.

  13. Strategies to improve recruitment to randomised trials.

    Science.gov (United States)

    Treweek, Shaun; Pitkethly, Marie; Cook, Jonathan; Fraser, Cynthia; Mitchell, Elizabeth; Sullivan, Frank; Jackson, Catherine; Taskila, Tyna K; Gardner, Heidi

    2018-02-22

    Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research. To quantify the effects of strategies for improving recruitment of participants to randomised trials. A secondary objective is to assess the evidence for the effect of the research setting (e.g. primary care versus secondary care) on recruitment. We searched the Cochrane Methodology Review Group Specialised Register (CMR) in the Cochrane Library (July 2012, searched 11 February 2015); MEDLINE and MEDLINE In Process (OVID) (1946 to 10 February 2015); Embase (OVID) (1996 to 2015 Week 06); Science Citation Index & Social Science Citation Index (ISI) (2009 to 11 February 2015) and ERIC (EBSCO) (2009 to 11 February 2015). Randomised and quasi-randomised trials of methods to increase recruitment to randomised trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. We excluded studies aiming to increase response rates to questionnaires or trial retention and those evaluating incentives and disincentives for clinicians to recruit participants. We extracted data on: the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used a risk difference to estimate the absolute improvement and the 95% confidence interval (CI) to describe the effect in individual trials. We assessed heterogeneity between trial results. We used GRADE to judge the certainty we had in the evidence coming from each comparison. We identified 68 eligible trials (24 new to this update) with more than 74,000 participants. There were 63 studies involving interventions aimed directly at trial participants, while five evaluated interventions aimed at people recruiting participants. All studies were in

  14. Generational Theory: Implications for Recruiting the Millennials

    National Research Council Canada - National Science Library

    Drago, James P

    2006-01-01

    .... Using generational theory it will review the characteristics beliefs values and attitudes of Generation X the Baby Boomers and the Millennial generation the target audience of the Army's current recruiting efforts...

  15. Social media as a recruitment strategy

    DEFF Research Database (Denmark)

    Wilson, Rhonda Lynne; Usher, Kim

    2017-01-01

    to a downturn in traditional forms of media, such as television, radio and printed newspapers, magazines and newsletters. Increasingly, the public is using social media instead of traditional media. This change has implications for the design of research and researchers will have to adapt their recruitment...... strategies to include social media, if they are to collect representative rich data that can be analysed and reliably inform the findings of research. AIM: To discuss the importance of rigorous research designs and to provide an example of a study that demonstrates how mental health researchers......, investigating help and support for young people's mental health, can adapt their traditional recruitment practices and applied this new knowledge to recruitment using social media. DISCUSSION: A carefully designed social media recruitment process was particularly useful in attracting informative participant...

  16. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.

    Science.gov (United States)

    Wang, Yixin; Jin, Yi; Mäe, Maarja Andaloussi; Zhang, Yang; Ortsäter, Henrik; Betsholtz, Christer; Mäkinen, Taija; Jakobsson, Lars

    2017-10-01

    Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin. © 2017. Published by The Company of Biologists Ltd.

  17. Land crabs as key drivers in tropical coastal forest recruitment

    Science.gov (United States)

    Lindquist, E.S.; Krauss, K.W.; Green, P.T.; O'Dowd, D. J.; Sherman, P.M.; Smith, T. J.

    2009-01-01

    Plant populations are regulated by a diverse assortment of abiotic and biotic factors that influence seed dispersal and viability, and seedling establishment and growth at the microsite. Rarely does one animal guild exert as significant an influence on different plant assemblages as land crabs. We review three tropical coastal ecosystems-mangroves, island maritime forests, and mainland coastal terrestrial forests-where land crabs directly influence forest composition by limiting tree establishment and recruitment. Land crabs differentially prey on seeds, propagules and seedlings along nutrient, chemical and physical environmental gradients. In all of these ecosystems, but especially mangroves, abiotic gradients are well studied, strong and influence plant species distributions. However, we suggest that crab predation has primacy over many of these environmental factors by acting as the first limiting factor of tropical tree recruitment to drive the potential structural and compositional organisation of coastal forests. We show that the influence of crabs varies relative to tidal gradient, shoreline distance, canopy position, time, season, tree species and fruiting periodicity. Crabs also facilitate forest growth and development through such activities as excavation of burrows, creation of soil mounds, aeration of soils, removal of leaf litter into burrows and creation of carbon-rich soil microhabitats. For all three systems, land crabs influence the distribution, density and size-class structure of tree populations. Indeed, crabs are among the major drivers of tree recruitment in tropical coastal forest ecosystems, and their conservation should be included in management plans of these forests. ?? 2009 Cambridge Philosophical Society.

  18. Ruled by Ubiquitylation: A New Order for Polycomb Recruitment

    Directory of Open Access Journals (Sweden)

    Yuri B. Schwartz

    2014-07-01

    Full Text Available Polycomb complexes are found in most cells, but they must be targeted to specific genes in specific cell types in order to regulate pluripotency and differentiation. The recruitment of Polycomb complexes to specific targets has been widely thought to occur in two steps: first, one complex, PRC2, produces histone H3 lysine 27 (H3K27 trimethylation at a specific gene, and then the PRC1 complex is recruited by its ability to bind to H3K27me3. Now, three new articles turn this model upside-down by showing that binding of a variant PRC1 complex and subsequent H2A ubiquitylation of surrounding chromatin is sufficient to trigger the recruitment of PRC2 and H3K27 trimethylation. These studies also show that ubiquitylated H2A is directly sensed by PRC2 and that ablation of PRC1-mediated H2A ubiquitylation impairs genome-wide PRC2 binding and disrupts mouse development.

  19. Land crabs as key drivers in tropical coastal forest recruitment.

    Science.gov (United States)

    Lindquist, Erin Stewart; Krauss, Ken W; Green, Peter T; O'Dowd, Dennis J; Sherman, Peter M; Smith, Thomas J

    2009-05-01

    Plant populations are regulated by a diverse assortment of abiotic and biotic factors that influence seed dispersal and viability, and seedling establishment and growth at the microsite. Rarely does one animal guild exert as significant an influence on different plant assemblages as land crabs. We review three tropical coastal ecosystems-mangroves, island maritime forests, and mainland coastal terrestrial forests-where land crabs directly influence forest composition by limiting tree establishment and recruitment. Land crabs differentially prey on seeds, propagules and seedlings along nutrient, chemical and physical environmental gradients. In all of these ecosystems, but especially mangroves, abiotic gradients are well studied, strong and influence plant species distributions. However, we suggest that crab predation has primacy over many of these environmental factors by acting as the first limiting factor of tropical tree recruitment to drive the potential structural and compositional organisation of coastal forests. We show that the influence of crabs varies relative to tidal gradient, shoreline distance, canopy position, time, season, tree species and fruiting periodicity. Crabs also facilitate forest growth and development through such activities as excavation of burrows, creation of soil mounds, aeration of soils, removal of leaf litter into burrows and creation of carbon-rich soil microhabitats. For all three systems, land crabs influence the distribution, density and size-class structure of tree populations. Indeed, crabs are among the major drivers of tree recruitment in tropical coastal forest ecosystems, and their conservation should be included in management plans of these forests.

  20. The Challenge of Recruiting Control Groups

    DEFF Research Database (Denmark)

    O'Connor, Maja

    2011-01-01

      Recruitment of a large and reliable control group is a challenge in psychological survey based research. The effect of recruitment styles and age on response-rate, data quality, and individual differences were investigated in a control group for a postal survey of elderly bereaved people....... This study was a direct reaction to the first recruitment attempt that had a 10% response rate. This study consisted of four groups of randomly selected elderly married people (65-81 years) receiving a postal questionnaire measuring depression, social support, coping style, adult attachment, life...... satisfaction, and personality factors. All groups were exposed to a set of general initiatives (customized introduction letter with university letterhead; self-addressed, prepaid envelope included; personally directed letter signed by the researcher; an assurance of confidentiality). Three groups were exposed...

  1. Enhancement of Marine Corps' Recruiting and Retention Programs

    National Research Council Canada - National Science Library

    Davis, Shalisa W

    2008-01-01

    Though the Marine Corps has historically met its recruitment and retention goals, recruiting has become more challenging and cultural indicators show that recruiting will become even more difficult in the future...

  2. Recruiting for addiction research via Facebook.

    Science.gov (United States)

    Thornton, Louise K; Harris, Keith; Baker, Amanda L; Johnson, Martin; Kay-Lambkin, Frances J

    2016-07-01

    This study aimed to examine the feasibility of recruiting participants to addiction research via Facebook. Participants were recruited via an advertisement on Facebook, a local research register and university psychology courses. Participants completed a self-report survey regarding substance use, history of mental health issues and current psychological distress. The 524 participants recruited via Facebook cost $1.86 per participant; and 418 participants were recruited via more traditional methods. There were significantly fewer women in the Facebook sample compared with the non-Facebook sample (χ(2)  = 196.61, P Facebook participants reported current use of tobacco (women: Facebook = 57%, non-Facebook = 21%, χ(2)  = 39.71, P Facebook = 62%, non-Facebook = 21%, χ(2)  = 32.429, P Facebook = 26%, non-Facebook = 7%, χ(2)  = 14.364, P Facebook = 46%, non-Facebook = 24%, χ(2)  = 6.765, P Facebook sample contained a higher percentage of high-severity cannabis users (women: Facebook = 24%, non-Facebook = 4%, χ(2)  = 18.12, P Facebook = 43%, non-Facebook = 16%, χ(2)  = 10.00, P Facebook, we were able to capture a greater proportion of people with high-severity substance use and mental health issues and were able to capture a greater and more severe range of substance use behaviours. This suggests social networking sites are efficient, cost-effective ways to recruit large numbers of participants, with relevant behaviours and conditions, to addiction research. [Thornton LK, Harris K, Baker AL, Johnson M, Kay-Lambkin FJ. Recruiting for addiction research via Facebook. Drug Alcohol Rev 2016;35:494-502]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  3. Interferon regulatory factor-1 together with reactive oxygen species promotes the acceleration of cell cycle progression by up-regulating the cyclin E and CDK2 genes during high glucose-induced proliferation of vascular smooth muscle cells.

    Science.gov (United States)

    Zhang, Xi; Liu, Long; Chen, Chao; Chi, Ya-Li; Yang, Xiang-Qun; Xu, Yan; Li, Xiao-Tong; Guo, Shi-Lei; Xiong, Shao-Hu; Shen, Man-Ru; Sun, Yu; Zhang, Chuan-Sen; Hu, Kai-Meng

    2013-10-14

    The high glucose-induced proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of diabetic vascular diseases. In a previous study, we confirmed that Interferon regulatory factor-1 (Irf-1) is a positive regulator of the high glucose-induced proliferation of VSMCs. However, the mechanisms remain to be determined. The levels of cyclin/CDK expression in two cell models involving Irf-1 knockdown and overexpression were quantified to explore the relationship between Irf-1 and its downstream effectors under normal or high glucose conditions. Subsequently, cells were treated with high glucose/NAC, normal glucose/H₂O₂, high glucose/U0126 or normal glucose/H₂O₂/U0126 during an incubation period. Then proliferation, cyclin/CDK expression and cell cycle distribution assays were performed to determine whether ROS/Erk1/2 signaling pathway was involved in the Irf-1-induced regulation of VSMC growth under high glucose conditions. We found that Irf-1 overexpression led to down-regulation of cyclin D1/CDK4 and inhibited cell cycle progression in VSMCs under normal glucose conditions. In high glucose conditions, Irf-1 overexpression led to an up-regulation of cyclin E/CDK2 and an acceleration of cell cycle progression, whereas silencing of Irf-1 suppressed the expression of both proteins and inhibited the cell cycle during the high glucose-induced proliferation of VSMCs. Treatment of VSMCs with antioxidants prevented the Irf-1 overexpression-induced proliferation of VSMCs, the up-regulation of cyclin E/CDK2 and the acceleration of cell cycle progression in high glucose conditions. In contrast, under normal glucose conditions, H₂O₂ stimulation and Irf-1 overexpression induced cell proliferation, up-regulated cyclin E/CDK2 expression and promoted cell cycle acceleration. In addition, overexpression of Irf-1 promoted the activation of Erk1/2 and when VSMCs overexpressing Irf-1 were treated with U0126, the specific Erk1/2 inhibitor

  4. Rethinking Recruitment: The Comprehensive and Strategic Recruitment of Secondary Science Teachers

    Science.gov (United States)

    Luft, Julie A.; Wong, Sissy S.; Semken, Steve

    2011-01-01

    The shortage of science teachers has spurred a discussion about their retention and recruitment. While discussion about retaining science teachers has increased dramatically in just the last few years, science teacher educators have not attended to the recruitment of science teachers with the same tenacity. This paper is our effort to initiate…

  5. Special Forces Recruiting: The Operational Need for Targeted Recruitment of First and Second Generation Americans

    Science.gov (United States)

    2008-12-01

    Indigenous forces were recruited and trained by the OSS to operate from bases deep behind Japanese lines. Since American agents in Burma would attract...Team ( CLT ) is comprised of the Commander (SF) and First Sergeant (79R), and although these individuals are not included as recruiters, they do act

  6. Social networks and regional recruitment of foreign labour: Firm recruitment methods and spatial sorting in Denmark

    DEFF Research Database (Denmark)

    Schmidt, Torben Dall; Jensen, Peter Sandholt

    2012-01-01

    This paper tests the hypothesis that social networks are crucial for regional recruitment and inflows of foreign labour. New survey data on 971 firms located in Region Southern Denmark show that the predominant recruitment method of foreign labour was through networks. Danish municipal data from...... that employee referrals and information about vacancies in local job markets are also important for foreign labour....

  7. Sales Training for Army Recruiter Success: Modeling the Sales Strategies and Skills of Excellent Recruiters

    Science.gov (United States)

    1987-11-01

    strategies used by excellent Army recruiters. Neurolinguistic programming (NLP) was used as the protocol for modeling performance and acquiring...Behavioral and Social Sciences 3001 Eisenhower Avenue, Alexandria, VA 22333-5600 10. PROGRAM ELEMENT. PROJECT. TASK ARE* 4 WORK UNIT...Modeling ’Expert knowledge,, Neurolinguistics Knowledge engineering; Recruiting Sales, &’ Sales cycle Sales skills Sales strategies 20

  8. Analysis of the 1996 DoD Recruiter Survey Comments

    National Research Council Canada - National Science Library

    Condon, Katherine

    1998-01-01

    ...; family preparation, goal pressures and achievement, the recruiting market, out-of-pocket expenses, improprieties in recruiting, support from superiors, satisfaction with leadership, job satisfaction...

  9. Using Simulation to Model Time Utilization of Army Recruiters

    National Research Council Canada - National Science Library

    Cordeiro, James

    1998-01-01

    .... In many cases, recruiting stations are geographically isolated from military bases, with recruiters often tolerating a high cost of living, crime, and other such adverse conditions that characterize...

  10. A novel c-Src recruitment pathway from the cytosol to focal adhesions.

    Science.gov (United States)

    Machiyama, Hiroaki; Yamaguchi, Tomoyuki; Watanabe, Tomonobu M; Fujita, Hideaki

    2017-07-01

    The role of myristoylation in the localization and catalytic activity of Src at focal adhesions was investigated by live-cell imaging and site-directed mutagenesis. Although the majority of activated Src molecules are localized at focal adhesions, it is unclear how activated Src molecules are recruited to focal adhesions. Because Src is activated at the cell membrane, translocation of Src to cell membranes is considered to be essential for its recruitment to focal adhesions. Membrane-targeting-deficient Src mutant SrcG2A localizes at focal adhesions, indicating direct recruitment of Src from cytosol to focal adhesions. Furthermore, directly recruited Src molecules are shown to enhance paxillin dynamics at focal adhesions. These results reveal that the regulation of Src activation and translocation is more complex than previously suggested. © 2017 Federation of European Biochemical Societies.

  11. Recruitment in Adult Basic Education, Handbook.

    Science.gov (United States)

    Mulvey, Mary C.

    The handbook contains general information about adult basic education (ABE) and publicity for programs in the Providence School Department in particular, complete with materials used for recruitment via posters, newspaper articles, radio, television, and mailed flyers. Problems and causes of adult illiteracy are briefly discussed followed by ABE…

  12. Studying leukocyte recruitment under flow conditions.

    Science.gov (United States)

    Parsons, Sean A; Jurzinsky, Christophe; Cuvelier, Susan L; Patel, Kamala D

    2013-01-01

    Leukocyte recruitment from the vasculature occurs under conditions of haemodynamic shear stress. The parallel plate flow chamber apparatus is an in vitro system that is widely used to study leukocyte recruitment under shear conditions. The flow chamber is a versatile tool for examining adhesive interactions, as it can be used to study a variety of adhesive substrates, ranging from monolayers of primary cells to isolated adhesion molecules, and a variety of adhesive particles, ranging from leukocytes in whole blood to antibody-coated latex beads. We describe here methods for studying leukocyte recruitment to cytokine-stimulated, transfected or transduced endothelial cells using both whole blood and isolated leukocyte suspensions. These methods enable multiple parameters to be measured, including the total number of recruited leukocytes, the percentage of leukocytes that are rolling or firmly adherent, and the percentage of leukocytes that have transmigrated. Although these methods are described for interactions between leukocytes and endothelial cells, they are broadly applicable to the study of interactions between many combinations of adhesive substrates and adhesive particles.

  13. Computational social dynamic modeling of group recruitment.

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Nina M.; Lee, Marinna; Pickett, Marc; Turnley, Jessica Glicken (Sandia National Laboratories, Albuquerque, NM); Smrcka, Julianne D. (Sandia National Laboratories, Albuquerque, NM); Ko, Teresa H.; Moy, Timothy David (Sandia National Laboratories, Albuquerque, NM); Wu, Benjamin C.

    2004-01-01

    The Seldon software toolkit combines concepts from agent-based modeling and social science to create a computationally social dynamic model for group recruitment. The underlying recruitment model is based on a unique three-level hybrid agent-based architecture that contains simple agents (level one), abstract agents (level two), and cognitive agents (level three). This uniqueness of this architecture begins with abstract agents that permit the model to include social concepts (gang) or institutional concepts (school) into a typical software simulation environment. The future addition of cognitive agents to the recruitment model will provide a unique entity that does not exist in any agent-based modeling toolkits to date. We use social networks to provide an integrated mesh within and between the different levels. This Java based toolkit is used to analyze different social concepts based on initialization input from the user. The input alters a set of parameters used to influence the values associated with the simple agents, abstract agents, and the interactions (simple agent-simple agent or simple agent-abstract agent) between these entities. The results of phase-1 Seldon toolkit provide insight into how certain social concepts apply to different scenario development for inner city gang recruitment.

  14. CERN is still recruiting - Pass it on!

    CERN Multimedia

    2001-01-01

    This year there are still 70 limited duration staff vacancies to fill. Although the Web is proving a very effective way of attracting candidates, CERN people can play their part in the recruitment drive. To find out how you can help, read on. Despite the electronic era, word-of-mouth communication is still doing a good job! Over the last year about 23% of staff applicants found out about our vacancies through personal contacts. The article published last year in the Bulletin (10.4.and 24.4.2000) about recruitment at CERN had a very good initial response from people ready to spread the word about recruitment programmes in schools, universities and at conferences. As the article pointed out, it is still really important for CERN personnel to feel involved in this process. EST Division is now preparing its own initiative to send their engineers and technicians back to their schools in different Member States to attract candidates. We invite you once again to join in with this effort. The recruitment office is re...

  15. maintainability of manpower system with restricted recruitment

    African Journals Online (AJOL)

    JERRY

    Maintainability is an aspect of manpower control that has to do with making a desired manpower structure to remain the ... when the promotion flow is controlled to induce the required change in manpower structure, or recruitment control when the ..... In this case, using MATLAB with w as given above, P satisfies. ′. ′. ′.

  16. maintainability of manpower system with restricted recruitment

    African Journals Online (AJOL)

    JERRY

    remain the same at the mth future accounting periods, Batholomew (1982). It is regarded as one-step maintainability if m = 1 or r–step maintainability if m = r. Manpower structures are maintained by management control over the factors of control, usually promotion flow and recruitment flow. Hence, in the literature, it is ...

  17. Recruiting International Students to Your Campus

    Science.gov (United States)

    McFadden, Cheryl; Maahs-Fladung, Cathy; Mallett, William

    2012-01-01

    The purpose of this paper was to determine what institutional, program, and recruitment characteristics influenced international students to attend institutions in the United States. Two hundred sixteen international students at a Southern public research university responded to the survey (53% response rate) from 56 countries representing 8…

  18. Violent Video Games Recruit American Youth

    Science.gov (United States)

    Lugo, William

    2006-01-01

    An expert on the sociology of video games highlights the power of this medium to popularize violence among children. But few are aware that some of the most technologically potent products are violent war games now being produced at taxpayer expense. These are provided free as a recruiting tool by the United States military. The author contends…

  19. Recruiting and Advising Challenges in Actuarial Science

    Science.gov (United States)

    Case, Bettye Anne; Guan, Yuanying Michelle; Paris, Stephen

    2014-01-01

    Some challenges to increasing actuarial science program size through recruiting broadly among potential students are identified. Possible solutions depend on the structures and culture of the school. Up to three student cohorts may result from partition of potential students by the levels of academic progress before program entry: students…

  20. Recruiting, hiring, and retaining good employees.

    Science.gov (United States)

    McHenry Martin, Caren

    2014-08-01

    More pharmacists and other health care professionals often feel unprepared when engaged in the hiring process. This can occur both when looking for a new job and when participating as part of the hiring team. In this article, experts in strategies for recruiting, hiring, and retaining employees provide insight into successful strategies for today's changing workplace.

  1. Maintainability of manpower system with restricted recruitment ...

    African Journals Online (AJOL)

    The maintainability of a manpower system is studied under a Markov framework. The classical method of controlling only one factor of flow is extended to highlight the case in which two factors are under control simultaneously. One special case of this extension, where recruitment of units faces partial embargo, is given, ...

  2. Recruiting and training labor for woods work

    Science.gov (United States)

    Fred C. Simmons

    1949-01-01

    This is the second in a series of papers about the supervisory part of the logging job. It deals with recruiting and training men for logging; it stresses the need for safety. The previous paper in the series (Station Paper 18) dealt with choosing methods and equipment; other papers planned will be about job lay-out, purchase of timber, and marketing timber products....

  3. language teacher recruitment in the French

    African Journals Online (AJOL)

    language teacher recruitment in the French secondary education system. Abstract. In France, secondary teachers are public sector employees. Becoming a language teacher in secondary education is subject to passing public competitive entry examinations. Preparation for these examinations is provided in College ...

  4. Recruitment Of International Students Into Cameroon Tertiary ...

    African Journals Online (AJOL)

    This paper highlights the importance of Cameroon\\'s tertiary institutions\\' cooperation links with other African Universities given the rebirth of Organisation of African Unity as African Union, and the New Partnership for Africa Development (NEPAD). The present system of recruiting international students is haphazardly been ...

  5. Recruiting and Selecting a New Superintendent. Revised.

    Science.gov (United States)

    Lewis, Edmund L., Ed.

    The recruitment and selection of a new superintendent is a difficult and time-consuming task. It is the single most critical responsibility of a school board. The decision will ultimately affect the entire education program of the district. Careful and thoughtful preparation, definition of orderly and effective procedures, conformity with ethical…

  6. Multidrug-resistant Tuberculosis in Military Recruits

    OpenAIRE

    Freier, Grace; Wright, Allen; Nelson, Gregory; Brenner, Eric; Mase, Sundari; Tasker, Sybil; Matthews, Karen L.; Bohnker, Bruce K.

    2006-01-01

    We conducted a tuberculosis contact investigation for a female military recruit with an unreported history of multidrug-resistant tuberculosis (MDRTB) and subsequent recurrence. Pertinent issues included identification of likely contacts from separate training phases, uncertainty on latent MDRTB infection treatment regimens and side effects, and subsequent dispersal of the contacts after exposure.

  7. 22 CFR 229.510 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... Relations AGENCY FOR INTERNATIONAL DEVELOPMENT NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS... recipient shall recruit members of the sex so discriminated against so as to overcome the effects of such... have the effect of discriminating on the basis of sex in violation of §§ 229.500 through 229.550. ...

  8. 31 CFR 28.510 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... SEX IN EDUCATION PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Employment in Education Programs or Activities Prohibited § 28.510 Recruitment. (a... such actions have the effect of discriminating on the basis of sex in violation of §§ 28.500 through 28...

  9. 34 CFR 106.23 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE... the effect of discriminating on the basis of sex in violation of this subpart. (Authority: Secs. 901... 34 Education 1 2010-07-01 2010-07-01 false Recruitment. 106.23 Section 106.23 Education...

  10. 10 CFR 1042.510 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... OF ENERGY (GENERAL PROVISIONS) NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS OR... recruit members of the sex so discriminated against so as to overcome the effects of such past or present... furnish as applicants only or predominantly members of one sex if such actions have the effect of...

  11. 7 CFR 15a.23 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... members of one sex, if such actions have the effect of discriminating on the basis of sex in violation of... of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Admission and Recruitment Prohibited...

  12. 22 CFR 146.510 - Recruitment.

    Science.gov (United States)

    2010-04-01

    ... Relations DEPARTMENT OF STATE CIVIL RIGHTS NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS OR... recruit members of the sex so discriminated against so as to overcome the effects of such past or present... furnish as applicants only or predominantly members of one sex if such actions have the effect of...

  13. 49 CFR 25.510 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... Office of the Secretary of Transportation NONDISCRIMINATION ON THE BASIS OF SEX IN EDUCATION PROGRAMS OR... recruit members of the sex so discriminated against so as to overcome the effects of such past or present... furnish as applicants only or predominantly members of one sex if such actions have the effect of...

  14. Online Resumes: Optimizing Design to Service Recruiters

    NARCIS (Netherlands)

    Furtmueller-Ettinger, Elfriede; Wilderom, Celeste P.M.; Mueller, Roland

    2010-01-01

    Despite the increasing number of publications in e-Recruiting, there is still scant research on the specific requirements of online resume fields, in particular from the recruiters’ perspective. In this paper, the fields for resume forms are investigated by analyzing literature, interviewing

  15. Lineage specific composition of cyclin D-CDK4/CDK6-p27 complexes reveals distinct functions of CDK4, CDK6 and individual D-type cyclins in differentiating cells of embryonic origin

    Czech Academy of Sciences Publication Activity Database

    Bryja, Vítězslav; Pacherník, J.; Vondráček, Jan; Souček, Karel; Čajánek, L.; Horváth, Viktor; Holubcová, Z.; Dvořák, Petr; Hampl, Aleš

    2008-01-01

    Roč. 41, č. 6 (2008), s. 875-893 ISSN 0960-7722 R&D Projects: GA AV ČR(CZ) 1QS500040507; GA ČR(CZ) GA301/05/0463; GA ČR(CZ) GA204/07/0834; GA MŠk(CZ) 1M0538 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : G1/S transition * cyclin D * embryonic cells differentiation Subject RIV: AQ - Safety, Health Protection, Human - Machine Impact factor: 2.423, year: 2008

  16. Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell–matrix adhesion

    Science.gov (United States)

    Fernández-Hernández, Rita; Rafel, Marta; Fusté, Noel P; Aguayo, Rafael S; Casanova, Josep M; Egea, Joaquim; Ferrezuelo, Francisco; Garí, Eloi

    2013-01-01

    The function of Cyclin D1 (CycD1) has been widely studied in the cell nucleus as a regulatory subunit of the cyclin-dependent kinases Cdk4/6 involved in the control of proliferation and development in mammals. CycD1 has been also localized in the cytoplasm, where its function nevertheless is poorly characterized. In this work we have observed that in normal skin as well as in primary cultures of human keratinocytes, cytoplasmic localization of CycD1 correlated with the degree of differentiation of the keratinocyte. In these conditions, CycD1 co-localized in cytoplasmic foci with exocyst components (Sec6) and regulators (RalA), and with β1 integrin, suggesting a role for CycD1 in the regulation of keratinocyte adhesion during differentiation. Consistent with this hypothesis, CycD1 overexpression increased β1 integrin recycling and drastically reduced the ability of keratinocytes to adhere to the extracellular matrix. We propose that localization of CycD1 in the cytoplasm during skin differentiation could be related to the changes in detachment ability of keratinocytes committed to differentiation. PMID:23839032

  17. Exploration of cell cycle regulation and modulation of the DNA methylation mechanism of pelargonidin: Insights from the molecular modeling approach.

    Science.gov (United States)

    Karthi, Natesan; Karthiga, Arumugasamy; Kalaiyarasu, Thangaraj; Stalin, Antony; Manju, Vaiyapuri; Singh, Sanjeev Kumar; Cyril, Ravi; Lee, Sang-Myeong

    2017-10-01

    Pelargonidin is an anthocyanidin isolated from plant resources. It shows strong cytotoxicity toward various cancer cell lines, even though the carcinogenesis-modulating pathway of pelargonidin is not yet known. One of our previous reports showed that pelargonidin arrests the cell cycle and induces apoptosis in HT29 cells. Flowcytometry and immunoblot analysis confirmed that pelargonidin specifically inhibits the activation of CDK1 and blocks the G2-M transition of the cell cycle. In addition, DNA fragmentation was observed along with induction of cytochrome c release-mediated apoptosis. Hence, the aim of the present study was to investigate the molecular mechanism of pelargonidin's action on cell cycle regulators CDK1, CDK4, and CDK6 as well as the substrate-binding domain of DNMT1 and DNMT3A, which regulate the epigenetic signals related to DNA methylation. The results of docking analysis, binding free energy calculation, and molecular dynamics simulation correlated with the experimental results, and pelargonidin showed a specific interaction with CDK1. In this context, pelargonidin may also inhibit the recognition of DNA and catalytic binding by DNMT1 and DNMT3A. The HOMO-LUMO analysis mapped the functional groups of pelargonidin. Prediction of pharmacological descriptors suggested that pelargonidin can serve as a multitarget inhibitor for cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits

    DEFF Research Database (Denmark)

    Nielsen, Eva-Maria D; Hansen, Lars; Stissing, Trine

    2005-01-01

    CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in ...

  19. 7 CFR 170.7 - Can I apply if I am not recruited?

    Science.gov (United States)

    2010-01-01

    ... UNDER THE AGRICULTURAL MARKETING ACT OF 1946 USDA FARMERS MARKET § 170.7 Can I apply if I am not... 7 Agriculture 3 2010-01-01 2010-01-01 false Can I apply if I am not recruited? 170.7 Section 170.7 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards...

  20. 45 CFR 1308.5 - Recruitment and enrollment of children with disabilities.

    Science.gov (United States)

    2010-10-01

    ... of children with disabilities in the Head Start service area including types of disabilities and... disabilities. 1308.5 Section 1308.5 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF... WITH DISABILITIES Social Services Performance Standards § 1308.5 Recruitment and enrollment of children...

  1. Ecological factors affecting Rainbow Smelt recruitment in the main basin of Lake Huron, 1976-2010

    Science.gov (United States)

    O'Brien, Timothy P.; Taylor, William W.; Roseman, Edward F.; Madenjian, Charles P.; Riley, Stephen C.

    2014-01-01

    Rainbow Smelt Osmerus mordax are native to northeastern Atlantic and Pacific–Arctic drainages and have been widely introduced throughout North America. In the Great Lakes region, Rainbow Smelt are known predators and competitors of native fish and a primary prey species in pelagic food webs. Despite their widespread distribution, importance as a prey species, and potential to negatively interact with native fish species, there is limited information concerning stock–recruitment relationships for Rainbow Smelt. To better understand recruitment mechanisms, we evaluated potential ecological factors determining recruitment dynamics for Rainbow Smelt in Lake Huron using data from bottom trawl catches. We specifically evaluated influence of stock size, environmental factors (water temperature, lake levels, and precipitation), and salmonine predation on the production of age-0 recruits from 1976 to 2010. Rainbow Smelt recruitment was negatively related to stock size exceeding 10 kg/ha, indicating that compensatory, density-dependent mortality from cannibalism or intraspecific competition was an important factor related to the production of age-0 recruits. Recruitment was positively related to spring precipitation suggesting that the amount of stream-spawning habitat as determined by precipitation was important for the production of strong Rainbow Smelt recruitment. Additionally, density of age-0 Rainbow Smelt was positively related to Lake Trout Salvelinus namaycush abundance. However, spawning stock biomass of Rainbow Smelt, which declined substantially from 1989 to 2010, was negatively associated with Lake Trout catch per effort suggesting predation was an important factor related to the decline of age-2 and older Rainbow Smelt in Lake Huron. As such, we found that recruitment of Rainbow Smelt in Lake Huron was regulated by competition with or cannibalism by older conspecifics, spring precipitation influencing stream spawning habitats, and predation by Lake Trout on

  2. Recruiting Service Officer and Recruiter, SDIs (Special Duty Identifiers) 0920/99500.

    Science.gov (United States)

    1987-04-01

    AFISC/DAP 2 HQ ATC/DPAE 1 1 HQ ATC/TTQ 2 1 HQ USAF/ MPPT 1 1 HQ USMC (CODE TPI) 1 NODAC 1 3250 TCHTW/TTGX (LACKLAND AFB TX) 5 5 5 5 3250 TCHTW/TTS...Personnel cluster: Conduct office visits Operate USAF Recruiting Service vehicles Control or direct recruiting efforts to meet group, squadron, or flight... Control or direct recruiting efforts to meet group, squadron, or flight program objectives Conduct office visits Counsel personnel on personal or

  3. Temporal distribution of CDK4, CDK6, D-type cyclins, and p27 in developing mouse oocytes

    Czech Academy of Sciences Publication Activity Database

    Kohoutek, J.; Dvořák, Petr; Hampl, Aleš

    2004-01-01

    Roč. 70, - (2004), s. 139-145 ISSN 0006-3363 R&D Projects: GA ČR GA204/01/0905; GA MŠk LN00A065 Institutional research plan: CEZ:AV0Z5039906; CEZ:MSM 432100001 Keywords : early development * gametogenesis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.550, year: 2004

  4. Epiphytic Recruitment of Schefflera abyssinica (A. Rich) Harms. and ...

    African Journals Online (AJOL)

    Epiphytic recruitment of trees on trees is a form of facilitation allowing trees to escape herbivory and abiotic stress. In terms of survival and reaching the upper canopy sooner, this form of recruitment may be more successful than recruitment from the ground. Hence epiphytic recruitment may play a major role in affecting plant ...

  5. 20 CFR 655.154 - Additional positive recruitment.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Additional positive recruitment. 655.154... recruitment. (a) Where to conduct additional positive recruitment. The employer must conduct positive recruitment within a multistate region of traditional or expected labor supply where the CO finds that there...

  6. Recruitment of bloom-forming cyanobacteria and its driving factors

    African Journals Online (AJOL)

    STORAGESEVER

    2008-12-29

    Dec 29, 2008 ... Based on most of the literature, this paper reviewed the progress made in following aspects: cognition to cyanobacteria recruitment, various traps for studying cyanobacteria recruitment in lakes, recruitment patterns of some species of cyanobacteria, and the driving factors for recruitment. Additionally,.

  7. Recruitment of bloom-forming cyanobacteria and its driving factors ...

    African Journals Online (AJOL)

    Based on most of the literature, this paper reviewed the progress made in following aspects: cognition to cyanobacteria recruitment, various traps for studying cyanobacteria recruitment in lakes, recruitment patterns of some species of cyanobacteria, and the driving factors for recruitment. Additionally, perspective studies of ...

  8. Recruitment of feces donors among blood donors

    DEFF Research Database (Denmark)

    Dahl Jørgensen, Simon Mark; Erikstrup, Christian; Dinh, Khoa Manh

    2018-01-01

    As the use of fecal microbiota transplantation (FMT) has gained momentum, an increasing need for continuous access to healthy feces donors has developed. Blood donors constitute a healthy subset of the general population and may serve as an appropriate group for recruitment. In this study, we...... investigated the suitability of blood donors as feces donors. In a prospective cohort study, we recruited blood donors onsite at a public Danish blood bank. Following their consent, the blood donors underwent a stepwise screening process: First, blood donors completed an electronic pre-screening questionnaire...... to rule out predisposing risk factors. Second, eligible blood donors had blood and fecal samples examined. Of 155 blood donors asked to participate, 137 (88%) completed the electronic pre-screening questionnaire, 16 declined, and 2 were excluded. Of the 137 donors who completed the questionnaire, 79 (58...

  9. The Recruitment Theory of Language Origins

    Science.gov (United States)

    Steels, Luc

    Tremendous progress has been made recently on the fascinating question of the origins and evolution of language (see e.g. (55), (7), (9), (31)). There is no widely accepted complete theory yet, but several proposals are on the table and observations and experiments are proceeding. This chapter focuses on the recruitment theory of language origins which we have been exploring for almost ten years now. This theory argues that language users recruit and try out different strategies for solving the task of communication and retain those that maximise communicative success and cognitive economy. Each strategy requires specific cognitive neural mechanisms, which in themselves serve a wide range of purposes and therefore may have evolved or could be learned independently of language.

  10. Tudor Staphylococcal Nuclease (Tudor-SN), a Novel Regulator Facilitating G1/S Phase Transition, Acting as a Co-activator of E2F-1 in Cell Cycle Regulation*

    Science.gov (United States)

    Su, Chao; Zhang, Chunyan; Tecle, Adiam; Fu, Xue; He, Jinyan; Song, Juan; Zhang, Wei; Sun, Xiaoming; Ren, Yuanyuan; Silvennoinen, Olli; Yao, Zhi; Yang, Xi; Wei, Minxin; Yang, Jie

    2015-01-01

    Tudor staphylococcal nuclease (Tudor-SN) is a multifunctional protein implicated in a variety of cellular processes. In the present study, we identified Tudor-SN as a novel regulator in cell cycle. Tudor-SN was abundant in proliferating cells whereas barely expressed in terminally differentiated cells. Functional analysis indicated that ectopic overexpression of Tudor-SN promoted the G1/S transition, whereas knockdown of Tudor-SN caused G1 arrest. Moreover, the live-cell time-lapse experiment demonstrated that the cell cycle of MEF−/− (knock-out of Tudor-SN in mouse embryonic fibroblasts) was prolonged compared with wild-type MEF+/+. We noticed that Tudor-SN was constantly expressed in every cell cycle phase, but was highly phosphorylated in the G1/S border. Further study revealed that Tudor-SN was a potential substrate of Cdk2/4/6, supportively, we found the physical interaction of endogenous Tudor-SN with Cdk4/6 in G1 and the G1/S border, and with Cdk2 in the G1/S border and S phase. In addition, roscovitine (Cdk1/2/5 inhibitor) or CINK4 (Cdk4/6 inhibitor) could inhibit the phosphorylation of Tudor-SN, whereas ectopic overexpression of Cdk2/4/6 increased the Tudor-SN phosphorylation. The underlying molecular mechanisms indicated that Tudor-SN could physically interact with E2F-1 in vivo, and could enhance the physical association of E2F-1 with GCN5 (a cofactor of E2F-1, which possesses histone acetyltransferase activity), and promote the binding ability of E2F-1 to the promoter region of its target genes CYCLIN A and E2F-1, and as a result, facilitate the gene transcriptional activation. Taken together, Tudor-SN is identified as a novel co-activator of E2F-1, which could facilitate E2F-1-mediated gene transcriptional activation of target genes, which play essential roles in G1/S transition. PMID:25627688

  11. Foreign workers recruiting policies in Japan.

    Science.gov (United States)

    Nagayama, T

    1996-01-01

    "This article presents the basic characteristics of the foreign workers recruiting policy in Japan, which consists [of] barring entry to unskilled workers, and confronts it with the actual tolerance for a large number of illegal unskilled workers. After a historical overview of the reasons for the current policy, the article examines elements which reveal that a seclusionist policy is based on mistaken assumptions and reviews policy options to deal with the issue of illegal migration." excerpt

  12. Do recruitment maneuvers simply improve oxygenation?

    OpenAIRE

    Valenza, Franco

    2010-01-01

    Recruitment maneuvers have been the subject of intense investigation. Their role in the acute care setting is debated given the lack of information on their influence on clinical outcomes. Oxygenation improvement is often a striking effect, together with changes of respiratory mechanics. However, hemodynamic compromise is frequently associated with the maneuver, sometimes even barotrauma. Another possible downside is bacterial translocation secondary to lung overdistention, as suggested by ex...

  13. Assessing a Science Graduate School Recruitment Symposium.

    Science.gov (United States)

    González-Espada, Wilson; Díaz-Muñoz, Greetchen; Feliú-Mójer, Mónica; Flores-Otero, Jacqueline; Fortis-Santiago, Yaihara; Guerrero-Medina, Giovanna; López-Casillas, Marcos; Colón-Ramos, Daniel A; Fernández-Repollet, Emma

    2015-12-01

    Ciencia Puerto Rico, a non-profit organization dedicated to promoting science, research and scientific education among Latinos, organized an educational symposium to provide college science majors the tools, opportunities and advice to pursue graduate degrees and succeed in the STEM disciplines. In this article we share our experiences and lessons learned, for others interested in developing large-scale events to recruit underrepresented minorities to STEM and in evaluating the effectiveness of these efforts.

  14. Assessing a Science Graduate School Recruitment Symposium

    Science.gov (United States)

    González-Espada, Wilson; Díaz-Muñoz, Greetchen; Feliú-Mójer, Mónica; Flores-Otero, Jacqueline; Fortis-Santiago, Yaihara; Guerrero-Medina, Giovanna; López-Casillas, Marcos; Colón-Ramos, Daniel A.; Fernández-Repollet, Emma

    2015-01-01

    Ciencia Puerto Rico, a non-profit organization dedicated to promoting science, research and scientific education among Latinos, organized an educational symposium to provide college science majors the tools, opportunities and advice to pursue graduate degrees and succeed in the STEM disciplines. In this article we share our experiences and lessons learned, for others interested in developing large-scale events to recruit underrepresented minorities to STEM and in evaluating the effectiveness of these efforts. PMID:26770074

  15. Recruiting Women Smokers: The Engineering of Consent

    OpenAIRE

    Brandt, Allan M.

    1996-01-01

    A range of social forces contributed to the effective recruitment of women to cigarette smoking in the crucial period between 1900 and 1940. Cigarette advertisers and public relations experts recognized the significance of womens changing roles and the rising culture of consumption, and worked to create specific meanings for the cigarette to make it appeal to women. The cigarette was a flexible symbol, with a remarkably elastic set of meanings; for women, it represented rebellious independenc...

  16. Finding Lawrence: Recruiting Talent for Unconventional Warfare

    Science.gov (United States)

    2011-06-01

    Recruitment of First and Second Generation Americans‖ (Master’s thesis, Naval Postgraduate School, December 2008), 16–18. 18 Ian D. Sutherland , Special...cfa08/NSW%20Conf.%20for%20America%202.pdf; Edwin P. Hoyt, SEALs at War (New York: Dell Publishing, 1993); Andrea Hsu, ―Navy SEALs Seek to Build Up Their...131 Ian D. W. Sutherland , Special Forces of the United States Army (San Jose, CA: R. James Bender Publishing, 1990), 119. 132 Beckwith and Knox

  17. Recruitment in a changing environment: the 2000s North Sea herring recruitment failure

    NARCIS (Netherlands)

    Payne, M.R.; Hatfield, E.M.C.; Dickey-Collas, M.; Falkenhaug, T.; Roeckmann, C.

    2009-01-01

    Environmentally induced change appears to be impacting the recruitment of North Sea herring (Clupea harengus). Despite simultaneously having a large adult population, historically low exploitation, and Marine Stewardship Council accreditation (implying sustainability), there have been an

  18. Creating a High-Touch Recruitment Event: Utilizing Faculty to Recruit and Yield Students

    Science.gov (United States)

    Freed, Lindsey R.; Howell, Leanne L.

    2018-01-01

    The following article describes the planning and implementation of a university student recruitment event that produced a high (new) student yield. Detailed descriptions of how staff and faculty worked together to plan and implement this event are described.

  19. Changing recruitment capacity in global fish stocks.

    Science.gov (United States)

    Britten, Gregory L; Dowd, Michael; Worm, Boris

    2016-01-05

    Marine fish and invertebrates are shifting their regional and global distributions in response to climate change, but it is unclear whether their productivity is being affected as well. Here we tested for time-varying trends in biological productivity parameters across 262 fish stocks of 127 species in 39 large marine ecosystems and high-seas areas (hereafter LMEs). This global meta-analysis revealed widespread changes in the relationship between spawning stock size and the production of juvenile offspring (recruitment), suggesting fundamental biological change in fish stock productivity at early life stages. Across regions, we estimate that average recruitment capacity has declined at a rate approximately equal to 3% of the historical maximum per decade. However, we observed large variability among stocks and regions; for example, highly negative trends in the North Atlantic contrast with more neutral patterns in the North Pacific. The extent of biological change in each LME was significantly related to observed changes in phytoplankton chlorophyll concentration and the intensity of historical overfishing in that ecosystem. We conclude that both environmental changes and chronic overfishing have already affected the productive capacity of many stocks at the recruitment stage of the life cycle. These results provide a baseline for ecosystem-based fisheries management and may help adjust expectations for future food production from the oceans.

  20. Compensatory effects of recruitment and survival when amphibian populations are perturbed by disease

    Science.gov (United States)

    Muths, E.; Scherer, R. D.; Pilliod, D.S.

    2011-01-01

    The need to increase our understanding of factors that regulate animal population dynamics has been catalysed by recent, observed declines in wildlife populations worldwide. Reliable estimates of demographic parameters are critical for addressing basic and applied ecological questions and understanding the response of parameters to perturbations (e.g. disease, habitat loss, climate change). However, to fully assess the impact of perturbation on population dynamics, all parameters contributing to the response of the target population must be estimated. We applied the reverse-time model of Pradel in Program mark to 6years of capture-recapture data from two populations of Anaxyrus boreas (boreal toad) populations, one with disease and one without. We then assessed a priori hypotheses about differences in survival and recruitment relative to local environmental conditions and the presence of disease. We further explored the relative contribution of survival probability and recruitment rate to population growth and investigated how shifts in these parameters can alter population dynamics when a population is perturbed. High recruitment rates (0??41) are probably compensating for low survival probability (range 0??51-0??54) in the population challenged by an emerging pathogen, resulting in a relatively slow rate of decline. In contrast, the population with no evidence of disease had high survival probability (range 0??75-0??78) but lower recruitment rates (0??25). Synthesis and applications.We suggest that the relationship between survival and recruitment may be compensatory, providing evidence that populations challenged with disease are not necessarily doomed to extinction. A better understanding of these interactions may help to explain, and be used to predict, population regulation and persistence for wildlife threatened with disease. Further, reliable estimates of population parameters such as recruitment and survival can guide the formulation and implementation of

  1. Recruitment and retention of participants for an international type 1 diabetes prevention trial

    DEFF Research Database (Denmark)

    Franciscus, Margaret; Nucci, Anita; Bradley, Brenda

    2014-01-01

    BACKGROUND: The Trial to Reduce Insulin Dependent Diabetes Mellitus in the Genetically at Risk (TRIGR) is the first multicenter international type 1 diabetes (T1D) prevention trial to be undertaken. A unique feature of TRIGR has been recruitment of eligible pregnant women and enrollment of newborns...... privacy regulations mid-trial. The majority of participants were recruited from primary care antenatal clinics located near the study centers and from a general hospital or pediatric center that was affiliated with a TRIGR Study center. Internet and magazine advertisements were found to be useful...

  2. We Can Recruit Minorities Into The Geosciences

    Science.gov (United States)

    O'Connell, S.

    2011-12-01

    Despite the dismal numbers, efforts to recruit minorities into the geosciences are improving, thanks in part to NSF's "Opportunities for Enhancing Diversity in the Geosciences" (OEDG) initiative. At Wesleyan University, a small liberal arts college in Connecticut, we have significantly increased our recruitment of minority students. Twenty percent (four students) of the class of 2013 are African American. Most of the recruitment is done on an individual basis and working in conjunction with the "Dean for Diversity and Student Engagement" and courting minority students in introductory classes. The Dean for Diversity and Student Engagement is aware of our interest in increasing diversity and that we are able to hire minority students during the academic year and through the summer with OEDG funds. When she identifies minority students who might be interested in the geosciences, she refers them to faculty in the Earth and Environmental Sciences Department. Our faculty can provide employment, mentoring and a variety of geo-related experiences. Courting students in introductory courses can include inviting them to lunch or other activity, and attending sports, theater or dance events in which they are participating. Not all efforts result in new majors. Courses in ancillary sciences may be stumbling blocks and higher grades in less demanding courses have lured some students into other majors. Nevertheless, we now have a large enough cohort of minority students so that minority students from other majors visit their friends in our labs. A critical mass? Even a student, who chooses another major, may continue an interest in geoscience and through outreach efforts and discussions with younger family members, may provide a bridge that becomes a conduit for future students.

  3. Recruitment in a changing environment: the 2000s North Sea herring recruitment failure

    DEFF Research Database (Denmark)

    Payne, Mark; Hatfield, E.M.C.; Dickey-Collas, M.

    2009-01-01

    an unprecedented 6 sequential years of poor juvenile production (recruitment). Analysis suggests that the poor recruitment arises during the larval overwintering phase, with recent survival rates greatly reduced. Contemporary warming of the North Sea has caused significant changes in the plankton community......, and a recently identified regime shift around 2000 shows close temporal agreement with the reduced larval survival. It is, therefore, possible that we are observing the first consequences of this planktonic change for higher trophic levels. There is no indication of a recovery in recruitment in the short term....... Fishing mortality is currently outside the agreed management plan, and forecasts show a high risk of the stock moving outside safe biological limits soon, potentially precipitating another collapse of the stock. However, bringing the realized fishing mortality back in line with the management plan would...

  4. E-recruiting Platforms: Features that Influence the Efficiency of Online Recruitment Systems

    Directory of Open Access Journals (Sweden)

    Ondina ROSOIU

    2016-01-01

    Full Text Available Twenty active e-recruitment platform users took part in this study for discovering the most asked for features in a web based hiring process. The respondents were chosen based on their history on such recruitment platforms. With the help of our Internet users we narrowed down the number of platforms, to research for outstanding features and tool efficiency, to five most impressive ones (e-jobs, hipo, bestjobs, LinkedIn, Freelancer. The results were as useful as we expected when we proposed an investigation related to the future of web recruiting platforms. They underlined in a specific manner that most of such web platform users need to have a professional and fully functional environment where they can list their accomplishments and experience and receive direct feedback from employers or employees. The study also shows in detail how much and why do users like to have certain functionalities when they are searching for a new job.

  5. RECRUITMENT AND PROFESSIONAL TRAINING OF CIVIL SERVANTS

    Directory of Open Access Journals (Sweden)

    Roxana Cristina RADU

    2014-06-01

    Full Text Available An ever increasing feature of public office is the way in which the recruitment and training of civil servants are controlled by legislation. Civil servants are a basic component of public administration but they are also important for labor law because civil service relations have the characteristics of an employment relationship and also specific features resulting from the rules of public law. The relevant expression of the interferences between public and private law for civil servants is recruitment and training. The originality of this article lies in the multidisciplinary character, combining elements of labor law, administrative law and human resources management, character reflected in the bibliography used. Another merit of this study is that the authors correlated the provisions of various laws: Constitution, Labor Code, Law no. 161/2003 on the transparency in exercising public dignities and public functions, Government Ordinance no. 137/2000 regarding the prevention and sanction of all discrimination forms, Government Ordinance no. 129/2000 concerning adults’ professional training.

  6. Excellence in Navy Recruiting: A Look at High Performing Navy Recruiting Districts

    Science.gov (United States)

    1985-12-01

    driven by a de ,.re detest losing; they like to compete and to be the best. Eveiyone in the dist:’ict win. An Area inlisted P’rograms Officer wants to...recruiting district assigned by recruiters, will stay excellent as long as the people The other side of administracion is are doing all the little things...communicate with the CO, communicators. Communication means via the chain of command. ’[he recrui- telling each person what is expected of ters go through

  7. NICHE WEBSITES AND ONLINE TOOLS USED IN RECRUITMENT

    Directory of Open Access Journals (Sweden)

    Beniamin G. BOŞCAI

    2015-04-01

    Full Text Available Based on technological evolution and a very large number of users, the Internet plays a key role in attracting talented employees which can generate competitive advantage for the organization. Therefore nowadays niche websites, specialised recruitment sites, become increasingly important. With the creation of such sites also appeared several applications for recruiting. The purpose of this paper is to analyze these sites and applications in order to determine the advantages and disadvantages of specialised recruitment websites (1, career sites of organizations (2 social professional sites (3 . Using these online recruitment tools lead to the development of e-recruitment. Our conclusion is that these websites do not represent yet a universal solution for organizations although the number of users is growing. For being successful in the recruitment process, recruiters have to combine niche websites in recruiting and not use only one type of niche websites.

  8. Qualitative and Quantitative Analysis for US Army Recruiting Input Allocation

    National Research Council Canada - National Science Library

    Brence, John

    2004-01-01

    .... An objective study of the quantitative and qualitative aspects of recruiting is necessary to meet the future needs of the Army, in light of strong possibilities of recruiting resource reduction...

  9. Successful recruitment to trials: findings from the SCIMITAR+ Trial.

    Science.gov (United States)

    Peckham, Emily; Arundel, Catherine; Bailey, Della; Callen, Tracy; Cusack, Christina; Crosland, Suzanne; Foster, Penny; Herlihy, Hannah; Hope, James; Ker, Suzy; McCloud, Tayla; Romain-Hooper, Crystal-Bella; Stribling, Alison; Phiri, Peter; Tait, Ellen; Gilbody, Simon

    2018-01-19

    Randomised controlled trials (RCT) can struggle to recruit to target on time. This is especially the case with hard to reach populations such as those with severe mental ill health. The SCIMITAR+ trial, a trial of a bespoke smoking cessation intervention for people with severe mental ill health achieved their recruitment ahead of time and target. This article reports strategies that helped us to achieve this with the aim of aiding others recruiting from similar populations. SCIMITAR+ is a multi-centre pragmatic two-arm parallel-group RCT, which aimed to recruit 400 participants with severe mental ill health who smoke and would like to cut down or quit. The study recruited primarily in secondary care through community mental health teams and psychiatrists with a smaller number of participants recruited through primary care. Recruitment opened in October 2015 and closed in December 2016, by which point 526 participants had been recruited. We gathered information from recruiting sites on strategies which led to the successful recruitment in SCIMITAR+ and in this article present our approach to trial management along with the strategies employed by the recruiting sites. Alongside having a dedicated trial manager and trial management team, we identified three main themes that led to successful recruitment. These were: clinicians with a positive attitude to research; researchers and clinicians working together; and the use of NHS targets. The overriding theme was the importance of relationships between both the researchers and the recruiting clinicians and the recruiting clinicians and the participants. This study makes a significant contribution to the limited evidence base of real-world cases of successful recruitment to RCTs and offers practical guidance to those planning and conducting trials. Building positive relationships between clinicians, researchers and participants is crucial to successful recruitment.

  10. Enlistment Supply, Recruiter Objectives, and the All-Volunteer Army

    Science.gov (United States)

    1984-09-01

    general consensus regarding the relative importance of factors affecting enlistment supply.’ This, failure stems, ini large part, from a fundamantal flaw...averaged for each recruiting area for the two-year period. The mean ratio was .92. That is, recruiters located in a iepresentative MEPS area managed to...internal points; To the extent that some recruiters and recruiter managers may be more motivated than’ others to exceed quotas, on’.. might expect a

  11. Using marketing theory to inform strategies for recruitment: a recruitment optimisation model and the txt2stop experience.

    Science.gov (United States)

    Galli, Leandro; Knight, Rosemary; Robertson, Steven; Hoile, Elizabeth; Oladapo, Olubukola; Francis, David; Free, Caroline

    2014-05-22

    Recruitment is a major challenge for many trials; just over half reach their targets and almost a third resort to grant extensions. The economic and societal implications of this shortcoming are significant. Yet, we have a limited understanding of the processes that increase the probability that recruitment targets will be achieved. Accordingly, there is an urgent need to bring analytical rigour to the task of improving recruitment, thereby increasing the likelihood that trials reach their recruitment targets. This paper presents a conceptual framework that can be used to improve recruitment to clinical trials. Using a case-study approach, we reviewed the range of initiatives that had been undertaken to improve recruitment in the txt2stop trial using qualitative (semi-structured interviews with the principal investigator) and quantitative (recruitment) data analysis. Later, the txt2stop recruitment practices were compared to a previous model of marketing a trial and to key constructs in social marketing theory. Post hoc, we developed a recruitment optimisation model to serve as a conceptual framework to improve recruitment to clinical trials. A core premise of the model is that improving recruitment needs to be an iterative, learning process. The model describes three essential activities: i) recruitment phase monitoring, ii) marketing research, and iii) the evaluation of current performance. We describe the initiatives undertaken by the txt2stop trial and the results achieved, as an example of the use of the model. Further research should explore the impact of adopting the recruitment optimisation model when applied to other trials.

  12. Virtual HRM: A Case of e-Recruitment

    DEFF Research Database (Denmark)

    Holm, Anna

    2009-01-01

    of the qualitative exploratory study conducted in Denmark in 2008-2009. It concludes that as organisational concept e-recruitment is not only about application of technology to recruitment tasks. The process of e-recruiting spans organisational boundaries and directed to and affected by external environment...

  13. Episodic recruitment of the rock oyster Saccostrea cucullata (Born ...

    African Journals Online (AJOL)

    An exceptionally good recruitment of the rock oyster Saccostrea cucullata is reported from the Transkei coast. Prior to 1989 individuals smaller than 20 mm accounted for less than 3% of the population. New recruits now account for between 25% and 48% of standing stock. This single recruitment, which is 6 to 31 times the ...

  14. Episodic recruitment of the rock oyster Saccostrea cucullata (Born ...

    African Journals Online (AJOL)

    1989-10-03

    Oct 3, 1989 ... An exceptionally good recruitment of the rock oyster Saccostrea cucullata is reported from the Transkei coast. Prior to 1989 individuals smaller than 20 mm accounted for less than 3% of the population. New recruits now account for between 25% and 48% of standing stock. This single recruitment, which is 6 ...

  15. 45 CFR 84.42 - Admissions and recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Admissions and recruitment. 84.42 Section 84.42... Education § 84.42 Admissions and recruitment. (a) General. Qualified handicapped persons may not, on the basis of handicap, be denied admission or be subjected to discrimination in admission or recruitment by...

  16. 38 CFR 18.442 - Admissions and recruitment.

    Science.gov (United States)

    2010-07-01

    ... recruitment. 18.442 Section 18.442 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... Postsecondary Education § 18.442 Admissions and recruitment. (a) General. Qualified handicapped persons may not... recruitment by a recipient. (b) Admission. In administering its admission policies, a recipient; (1) May not...

  17. 45 CFR 605.42 - Admissions and recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Admissions and recruitment. 605.42 Section 605.42... Postsecondary Education § 605.42 Admissions and recruitment. (a) General. Qualified handicapped persons may not... recruitment by a recipient to which this subpart applies. (b) Admissions. In administering its admission...

  18. 15 CFR 8b.20 - Admission and recruitment.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Admission and recruitment. 8b.20... Secondary Education § 8b.20 Admission and recruitment. (a) General. Qualified handicapped may not, on the basis of handicap, be denied admission or be subjected to discrimination in admission or recruitment by...

  19. 45 CFR 1170.42 - Admissions and recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Admissions and recruitment. 1170.42 Section 1170... FEDERALLY ASSISTED PROGRAMS OR ACTIVITIES Postsecondary Education § 1170.42 Admissions and recruitment. (a... subjected to discrimination in admission or recruitment by a recipient to which this subpart applies. (b...

  20. 20 CFR 655.15 - Required pre-filing recruitment.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Required pre-filing recruitment. 655.15... States (H-2B Workers) § 655.15 Required pre-filing recruitment. (a) Time of filing of application. An... recruitment steps set forth in this section have been fully satisfied, except where specifically exempted from...

  1. Recruitment to Intellectual Disability Research: A Qualitative Study

    Science.gov (United States)

    Nicholson, L.; Colyer, M.; Cooper, S. -A.

    2013-01-01

    Background: Difficulties in the recruitment of adults with intellectual disability (ID) to research studies are well described but little studied. The aim of this study was to investigate the difficulties in recruiting to a specific research project, in order to inform future recruitment to ID research. Methods: Individual semi-structured…

  2. 34 CFR 104.42 - Admissions and recruitment.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Admissions and recruitment. 104.42 Section 104.42... ASSISTANCE Postsecondary Education § 104.42 Admissions and recruitment. (a) General. Qualified handicapped... admission or recruitment by a recipient to which this subpart applies. (b) Admissions. In administering its...

  3. 22 CFR 142.42 - Admissions and recruitment.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Admissions and recruitment. 142.42 Section 142... and recruitment. (a) General. Qualified handicapped persons may not, on the basis of handicap, be denied admission or be subjected to discrimination in admission or recruitment by a recipient to which...

  4. 20 CFR 655.158 - Duration of positive recruitment.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Duration of positive recruitment. 655.158 Section 655.158 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY... recruitment. Except as otherwise noted, the obligation to engage in positive recruitment described in §§ 655...

  5. Recruitment strategies and colony size in social insects

    NARCIS (Netherlands)

    Planque, R.; van den Berg, G.J.B.; Franks, N.R.

    2010-01-01

    Ants use a great variety of recruitment methods to forage for food or find new nests, including tandem running, group recruitment and scent trails. It has been known for some time that there is a loose correlation across many taxa between species-specific mature colony size and recruitment method.

  6. 7 CFR 15b.30 - Admissions and recruitment.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Admissions and recruitment. 15b.30 Section 15b.30... ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE Postsecondary Education § 15b.30 Admissions and recruitment... be subjected to discrimination in admission or recruitment by a recipient to which this subpart...

  7. Recruitment and Retention of LGBTIQ Astronomers

    Science.gov (United States)

    Dixon, William Van Dyke

    2012-01-01

    While lesbian, gay, bisexual, transgender, intersex, or questioning (LGBTIQ) astronomers face many of the same workplace challenges as women and racial/ethnic minorities, from implicit bias to overt discrimination, other challenges are unique to this group. An obvious example is the absence at many institutions of health insurance and other benefits for the same-sex domestic partners of their employees. More subtle is the psychological toll paid by LGBTIQ astronomers who remain "in the closet," self-censoring every statement about their personal lives. Paradoxically, the culture of the physical sciences, in which sexuality, gender identity, and gender expression are considered irrelevant, can discourage their discussion, further isolating LGBTIQ researchers. Addressing these challenges is not just a matter of fairness; it is an essential tool in the recruitment and retention of the brightest researchers and in assuring their productivity. We will discuss these issues and what individuals and departments can to make their institutions more welcoming to their LGBTIQ colleagues.

  8. Recruiting women smokers: the engineering of consent.

    Science.gov (United States)

    Brandt, A M

    1996-01-01

    A range of social forces contributed to the effective recruitment of women to cigarette smoking in the crucial period between 1900 and 1940. Cigarette advertisers and public relations experts recognized the significance of women's changing roles and the rising culture of consumption, and worked to create specific meanings for the cigarette to make it appeal to women. The cigarette was a flexible symbol, with a remarkably elastic set of meanings; for women, it represented rebellious independence, glamour, seduction, and sexual allure, and served as a symbol for both feminists and flappers. The industry, with the help of advertisers and public relations experts, effectively engineered consent for women as smokers. The "engineering of consent" has a role to play in smoking cessation, since negative meanings for the cigarette can be engineered as well.

  9. Documenting operations accounting for recruitment costs

    Directory of Open Access Journals (Sweden)

    Samchuk K.I.

    2017-03-01

    Full Text Available The article analyzes the activities of domestic consulting companies in partial provision of recruitment, it was found that these services are quite expensive cost. What prompted changes to the work plan account at partial cost of the company with the corresponding distinguishing them for production, administration, distribution costs. For efficient organization of analytical accounting invited to approve classifiers business costs as application of the accounting policies while bringing them into computer information system of accounting as a guide. A form of primary documents that serve as documentary proof of performance of the contract of service of searching. The set details of the proposed forms of primary documents directed to presenting information of financial, economic and legal nature.

  10. College and University Minority Recruitment: Barriers, Recruitment Principles, and Design Guidelines.

    Science.gov (United States)

    Oliver, J.; Brown, Lester B.

    1988-01-01

    Identifies six principles which will assist in recruitment activities of students from minority groups. Describes a four-phase framework for action which includes gauging the environment and building a support structure. Concludes ways must be found to reverse trend of declining Black enrollment. (ABL)

  11. The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.

    Science.gov (United States)

    Pack, Thomas F; Orlen, Margo I; Ray, Caroline; Peterson, Sean M; Caron, Marc G

    2018-02-27

    The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways. Therefore βarr recruitment appears to be intimately tied to G protein activation via GRKs. Here, we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on βarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or βarrs as well as a βarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the βarr-preferring D2R achieves βarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the βarr-preferring D2R and also contributes to βarr recruitment at the WT D2R. Additionally, we found an additive interaction between the βarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving βarr-biased signaling. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Coral recruitment patterns in the Florida Keys

    Directory of Open Access Journals (Sweden)

    Alison L Moulding

    2005-05-01

    Full Text Available This study examines scleractinian zooxanthellate coral recruitment patterns in the Florida Keys to determine if differences in density or community composition exist between regions.From July to September 2002,nine patch reefs,three in each of the upper,middle and lower Keys,were surveyed for coral recruits (colonies Se examina los patrones de reclutamiento de corales escleractinios zooxantelados en los Cayos de la Florida para determinar si existen diferencias en densidad o composición de la comunidad en diferentes regiones.Entre julio y setiembre del 2002,se inventariaron los reclutas (colonias de <5 cm de diámetrousando cuadrantes y transectos al azar en nueve "parches "arrecifales:tres en los cayos del norte,tres en los del medio y tres en los del sur.Todos fueron numerados,medidos e identificados a nivel de género.Se observaron catorce géneros:entre cinco y 13 por sitio.Las densidades tuvieron un ámbito de 6.29 ±1.92 (promedio ±DSa 39.08 ±4.53 reclutas m-2, con diferencias estadísticamente significativas entre sitios y entre regiones.La densidad de reclutas en los cayos del norte fue significativamente menor que en los demás.Los cayos del norte tuvieron menor diversidad y diferente distribución de tamaños de reclutas.La mayoría de los reclutas eran de especies de escleractinios no masivas,las cuales contribuyen relativamente poco al proceso de crecimiento del arrecife,algo parecido a lo informado en otros estudios. Se encontraron menos reclutas de especies masivas en los cayos del norte.El patrón de reclutamiento en los arrecifes de los cayos del norte podría inhibir potencialmente la recuperación tras "impactos "y perturbaciones.

  13. [Pathology in social media networks. Recruitment campaign].

    Science.gov (United States)

    Alcaraz Mateos, Eduardo; Guerra Pastrián, Laura; Pijuan Andújar, Lara; López Solache, Laura; Zucchiatti, Adriana; García Ángel, Rubén; Prieto Cuadra, Juan Daniel; Labiano Miravalles, Tania; Carvalho, Rita; Gardner, Jerad M; Terrádez, Cristina; de Álava, Enrique

    Pathology is a speciality that is often poorly understood, not only by the general public, but also by clinicians. However, the recent widespread use of social media provides an opportunity to increase the visibility and comprehension of our profession. A working group was formed to carry out this task. The members of the Spanish Society of Pathology were contacted through its Communication and Social Projection Subcommittee to engage in the campaign #IWantYouForSEAP, to form a network on Twitter. The recruitment period was one month (August, 2016). The resulting project, developed during the XXVIII Congress of the SEAP-IAP, was registered using the analytical tools Symplur and Tweet Binder. 32 applications (29 pathologists, 2 histotechnicians, 1 administrative personnel) were received from all over Spain, including participants from 14 of the 17 Autonomous Regions, from 22 cities and 25 medical centres. The activity in relation to the hashtag #SEAP2017V used in the congress included 685 participants with 6704 tweets and 8,837,435 impressions. 28 of the 32 recruited by the #IWantYouForSEAP campaign participated, contributing with 2410 tweets, and generating 2,090,423 impressions (36% and 24% of the total, respectively). It is possible to promote and motivate teamwork within our discipline through social media networks. This preliminary experience of the use of social media networks in our scientific community has had encouraging results which have raised high expectations among participants. An appropriate use of social media networks could help to narrow the gap between pathologists and society. Copyright © 2017 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Fibrinogen modulates leukocyte recruitment in vivo during the acute inflammatory response.

    Science.gov (United States)

    Vitorino de Almeida, V; Silva-Herdade, A; Calado, A; Rosário, H S; Saldanha, C

    2015-01-01

    Besides playing an important role in blood hemostases, fibrinogen also regulates leukocyte function in inflammation. Our previous in vitro studies showed that the adhesive behaviour of the neutrophil is modulated by soluble fibrinogen when present at a physiological concentration. This led us to propose that this plasma glycoprotein might further influence leukocyte recruitment in vivo and thus contribute to the inflammatory response. To address this in vivo, leukocyte recruitment was here investigated under acute inflammatory conditions in the absence of soluble fibrinogen in the blood circulation. For such, intravital microscopy on mesentery post-capillary venules was performed on homozygous fibrinogen α chain-deficient mice ((α-/-) mice). Acute inflammatory states were induced by perfusing platelet activating factor (PAF) over the exposed tissue. As control animals, two groups of mice expressing soluble fibrinogen in circulation were used, namely, C57BL/6 wild type animals and heterozygous fibrinogen α chain-deficient mice ((α+/-) mice). Under acute inflammatory conditions, an abnormal pattern of recruitment was observed for leukocytes in homozygous (α-/-) mice in comparison to both control groups. In fact, the former exhibited a significantly decreased number of rolling leukocytes that nevertheless, migrated with increased rolling velocities when compared to leukocytes from control animals. Consistently, homozygous mice further displayed a diminished number of adherent leukocytes than the other groups. Altogether our observations led us to conclude that leukocyte recruitment in homozygous (α-/-) mice is compromised what strongly suggests a role for soluble fibrinogen in leukocyte recruitment in inflammation.

  15. REST-mediated recruitment of polycomb repressor complexes in mammalian cells

    DEFF Research Database (Denmark)

    Dietrich, Nikolaj; Lerdrup, Mads; Landt, Eskild

    2012-01-01

    Polycomb Repressive Complex (PRC) 1 and PRC2 regulate genes involved in differentiation and development. However, the mechanism for how PRC1 and PRC2 are recruited to genes in mammalian cells is unclear. Here we present evidence for an interaction between the transcription factor REST, PRC1......, and increased gene expression. Genome-wide analysis of Polycomb binding in Rest¿/¿ and Eed¿/¿ mouse embryonic stem (mES) cells showed that Rest was required for PRC1 recruitment to a subset of Polycomb regulated neuronal genes. Furthermore, we found that PRC1 can be recruited to Rest binding sites independently...... of CpG islands and the H3K27Me3 mark. Surprisingly, PRC2 was frequently increased around Rest binding sites located in CpG-rich regions in the Rest¿/¿ mES cells, indicating a more complex interplay where Rest also can limit PRC2 recruitment. Therefore, we propose that Rest has context...

  16. The Yersinia pseudotuberculosis outer membrane protein Ail recruits the human complement regulatory protein factor H.

    Science.gov (United States)

    Ho, Derek K; Riva, Rauna; Skurnik, Mikael; Meri, Seppo

    2012-10-01

    Previous investigations characterizing the mechanism(s) of complement resistance in Yersinia pseudotuberculosis showed that the outer membrane protein Ail can functionally recruit the regulator of the classical and lectin pathways of complement, C4b-binding protein. In this study, we extend these observations and show that Ail can also recruit the regulator of the alternative pathway (AP), factor H (fH). Binding to fH was dependent on Ail expression and observed in the context of full-length LPS. Inactivation of ail resulted in loss of fH binding. Ail expression conferred resistance to AP-mediated killing. Bound fH was functional as a cofactor for factor I-mediated cleavage and inactivation of C3b. Ail alone is sufficient to mediate fH binding and resistance to AP-mediated killing, because Ail expression in a laboratory Escherichia coli strain conferred both of these phenotypes. Binding was specific and inhibited by increasing heparin and NaCl concentrations. Using a panel of fH recombinant fragments, we observed that both short consensus repeats 5-7 and 19-20 regions are responsible for mediating the interaction with Ail. Collectively, these results suggest that fH recruitment is an additional mechanism of complement resistance of Ail. Recruitment of both fH and C4BP by Ail may confer Y. pseudotuberculosis with the ability to resist all pathways of complement activation.

  17. Effects of resource availability on seedling recruitment in a fire-maintained savanna.

    Science.gov (United States)

    Iacona, Gwenllian D; Kirkman, L Katherine; Bruna, Emilio M

    2010-05-01

    The herbaceous ground cover of the longleaf pine ecosystem harbors the highest plant species richness in North America, with up to 50 species per square meter, but the mechanisms that regulate this diversity are not well understood. In this system, variability in seedling recruitment events may best explain the extremely high small-scale species richness and its relationship to soil moisture and system net primary productivity. To understand the potential mechanistic controls on species richness, we used a long-term resource manipulation study across a natural soil moisture gradient to assess environmental controls on seedling recruitment. We considered the availability of resources to be an indicator of seedling safe-site supply, and also manipulated seed availability to examine the relative importance of recruitment limitations on seedling diversity. We found that water availability regulated the number of species in the seedling community regardless of the underlying natural moisture gradient, and that this effect may result from differential responses of seedling guilds to resource availability. Water supply was more important than seed supply in determining seedling establishment, suggesting that appropriate sites for regeneration are a factor limiting seedling success. This is the first study that shows that the episodic supply of microsites for recruitment could influence species richness in the highly threatened and biodiverse longleaf pine savanna.

  18. Recruitment strategies should not be randomly selected: empirically improving recruitment success and diversity in developmental psychology research

    Science.gov (United States)

    Sugden, Nicole A.; Moulson, Margaret C.

    2015-01-01

    Psychological and developmental research have been critiqued for the lack of diversity of research samples. Because differences in culture, race, and ethnicity can influence participant behavior, limited diversity limits the generalizability of the findings. These differences may also impact how participants behave in response to recruitment attempts, which suggests that recruitment itself may be leveraged to increase sample diversity. The goal of the current study was to determine what factors, within a recruitment interaction, could be leveraged to increase success and diversity when recruiting families with children for developmental research. Study 1 found three factors influenced success: (1) recruitment was more successful when other potential participants were also interested (i.e., recruiters were busy), (2) recruiters of particular races were more successful than recruiters of other races, and (3) differences in success were related to what the recruiter said to engage the potential participant (i.e., the script). The latter two factors interacted, suggesting some recruiters were using less optimal scripts. To improve success rates, study 2 randomly assigned scripts to recruiters and encouraged them to recruit more vigorously during busy periods. Study 2 found that two factors influenced success: (1) some scripts were more successful than others and (2) we were more successful at recruiting non-White potential participants than White participants. These two interacted, with some scripts being more successful with White and other scripts being more successful with non-White families. This intervention significantly increased recruitment success rate by 8.1% and the overall number of families recruited by 15.3%. These findings reveal that empirically evaluating and tailoring recruitment efforts based on the most successful strategies is effective in boosting diversity through increased participation of children from non-White families. PMID:25972829

  19. Recruited renin-containing renal microvascular cells demonstrate the calcium paradox regulatory phenotype

    Directory of Open Access Journals (Sweden)

    MacGriff S

    2014-01-01

    Full Text Available Spencer MacGriff,1 Richard E Woo,1 M Cecilia Ortiz-Capisano,1 Douglas K Atchison,1,2 William H Beierwaltes1,2 1Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, 2Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA Abstract: Renin is the critical regulatory enzyme for production of angiotensin (Ang-II, a potent vasoconstrictor involved in regulating blood pressure and in the pathogenesis of hypertension. Chronic sodium deprivation enhances renin secretion from the kidney, due to recruitment of additional cells from the afferent renal microvasculature to become renin-producing rather than just increasing release from existing juxtaglomerular (JG cells. JG cells secrete renin inversely proportional to extra- and intracellular calcium, a unique phenomenon characteristic of the JG regulatory phenotype known as the “calcium paradox.” It is not known if renin secreted from recruited renin-containing cells is regulated similarly to native JG cells, and therefore acquires this JG cell phenotype. We hypothesized that non-JG cells in renal microvessels recruited to produce renin in response to chronic dietary sodium restriction would demonstrate the calcium paradox, characteristic of the JG cell phenotype. Histology showed recruitment of upstream arteriolar renin in response to sodium restriction compared to normal-diet rats. Renin fluorescence intensity increased 53% in cortices of sodium-restricted rats (P<0.001. We measured renin release from rat afferent microvessels, isolated using iron oxide nanopowder and incubated in either normal or low-calcium media. Basal renin release from normal sodium-diet rat microvessels in normal calcium media was 298.1±44.6 ng AngI/mL/hour/mg protein, and in low-calcium media increased 39% to 415.9±71.4 ng AngI/mL/hour/mg protein (P<0.025. Renin released from sodium-restricted rat microvessels increased 50% compared to samples from

  20. [Generation Y : recruitment, retention and development].

    Science.gov (United States)

    Schmidt, C E; Möller, J; Schmidt, K; Gerbershagen, M U; Wappler, F; Limmroth, V; Padosch, S A; Bauer, M

    2011-06-01

    There is a significant shortage of highly qualified personnel in medicine, especially skilled doctors and nurses. This shortage of qualified labor has led to competition between hospitals. Analyzing the circumstances of the competition, nurses and doctors of the so-called generation Y are of importance. Recruitment and retention of these staff members will become a critical success factor for hospitals in the future. An internet search was conducted using the key words "generation Y and medicine, demography, personnel and hospitals". A search in Medline/pubmed for scientific studies on the topics of labor shortage was performed using the key words "personnel, shortage doctors, generation X, baby boomer, personnel and demographic changes, staff". Finally, sources from public institutions and academic medical societies were analyzed. The data were sorted by main categories and relevance for hospitals. Statistical analysis was done using descriptive measures. The analysis confirmed the heterogeneous and complex flood of information on the topic demography and generation. A comparison of the generations showed that they can be separated into baby boomers (born 1946-1964 live to work), generation X (born 1965-1980 work to live) and generation Y (born 1981 and after, live while working). Members of generation Y "live while working" are oriented to competence and less with hierarchies. They exchange information using modern communication methods and within networks. Internet and computers are part of their daily routine. Employees of generation Y challenge leadership in hospitals by increasing the demands. However, generation Y can significantly increase professionalization and competitiveness for hospitals.

  1. Islamist groups in the UK and recruitment

    Directory of Open Access Journals (Sweden)

    Mohammed Ilyas

    2013-09-01

    Full Text Available Since 2001 and 7/7 the search to find out why and how Muslims born in Europe join political and violence orientated Islamist groups has occupied policy makers and social scientist. The search has produced explanations that suggest social grievance, Islam and physiological problems are the motivations for why some Muslims join and act on behalf of Islamist groups in the UK. However, the approaches tend not to focus the role emotions generated from events that involve Muslim suffering play in some individuals becoming interested in acquiring and acting upon them. These events are often experienced variously by Muslims living in Europe through the media and are used by Islamist groups as resources to recruit. Consequently, this paper is based on interviews carried out with Islamists in the UK and tentatively discusses two process that take into account the emotional effect of events that concern Muslims in order to make sense of how some Muslims become compelled to acquire extreme ideas, act upon extreme ideas (independently or behalf of a group or join Islamist groups.

  2. Compliance with donor age recommendations in oocyte donor recruitment advertisements in the USA.

    Science.gov (United States)

    Alberta, Hillary B; Berry, Roberta M; Levine, Aaron D

    2013-04-01

    IVF using donated oocytes offers benefits to many infertile patients, yet the technique also raises a number of ethical concerns, including worries about potential physical and psychological risks to oocyte donors. In the USA, oversight of oocyte donation consists of a combination of federal and state regulations and self-regulatory guidelines promulgated by the American Society for Reproductive Medicine. This study assesses compliance with one of these self-regulatory guidelines - specifically, ASRM's preferred minimum age for donors of 21. To assess compliance, 539 oocyte donor recruitment advertisements from two recruitment channels (Craigslist and college newspapers) were collected and evaluated. Of these, 61% in the Craigslist dataset and 43% in the college newspaper dataset listed minimum ages between 18 and 20, which is inconsistent with ASRM's preferred minimum age recommendation of 21. Advertisements placed by oocyte donor recruitment agencies were more likely than advertisements placed by clinics to specify minimum ages between 18 and 20. These results indicate that ASRM should evaluate and consider revising its donor age guidelines. IVF using donated human eggs can help many patients who have difficulty having children. However, the technique also raises ethical concerns, including concerns about potential physical and psychological harms to egg donors. In the USA, oversight of egg donation relies on a combination of federal and state regulation and professional self-regulation. Governmental regulations address only limited aspects of egg donation, such as the potential spread of infectious diseases and the reporting of success rates, leaving voluntary guidelines developed by an association of medical professionals to address most issues, including ethical concerns raised by the practice. One of these voluntary guidelines recommends that egg donors should be at least 21 years of age. In this article, we analysed 539 egg donor recruitment advertisements

  3. Hrs recruits clathrin to early endosomes

    OpenAIRE

    Raiborg, Camilla; Grønvold Bache, Kristi; Mehlum, Anja; Stang, Espen; Stenmark, Harald

    2001-01-01

    The hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs, has been implicated in intracellular trafficking and signal transduction. Hrs contains a phosphatidylinositol 3-phosphate-binding FYVE domain that contributes to its endosomal targeting. Here we show that Hrs and EEA1, a FYVE domain protein involved in endocytic membrane fusion, are localized to different regions of early endosomes. We demonstrate that Hrs co-localizes with clathrin, and that the C-terminus of Hrs contains...

  4. Identifying British Army infantry recruit population characteristics using biographical data.

    Science.gov (United States)

    Kiernan, M D; Arthur, A; Repper, J; Mukhuty, S; Fear, N T

    2016-04-01

    The infantry accounts for more than a quarter of the British Army but there is a lack of data about the social and educational background of its recruits. To provide an insight into British Army infantry recruits' personal, social and educational background prior to enlistment. The study sample consisted of infantry recruits who enlisted into the British Army School of Infantry. Each recruit completed a 95-item biographical questionnaire. Descriptive statistics were used to describe the sample in terms of demographic, physical, personal, social and educational attributes. The study sample consisted of 1000 male recruits. Over half of the recruits were consuming alcohol at a hazardous or harmful level prior to enlistment and 60% of recruits had used cannabis prior to joining the Army. Academic attainment was low, with the majority of recruits achieving GCSE grade C and below in most subjects, with 15% not taking any examinations. Over half the recruits had been in trouble with the police and either been suspended or expelled from school. Substance misuse and poor behaviour are highly prevalent among recruits prior to enlistment. Taken alongside existing evidence that some of these problems are commonplace among personnel in regular service, the assumption that the British Army infantry is, in itself, a cause of these behaviours should be questioned. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Successful subject recruitment for a prostate cancer behavioral intervention trial.

    Science.gov (United States)

    Heiney, Sue P; Arp Adams, Swann; Drake, Bettina F; Bryant, Lisa H; Bridges, Lynne; Hebert, James R

    2010-08-01

    Inadequate participant recruitment, which may lead to unrepresentative study samples that threaten a study's validity, is often a major challenge in the conduct of research studies. The purpose of this article is to describe the development and implementation of a recruitment plan and evaluate the different recruitment strategies for a prostate cancer behavioral intervention trial. Our recruitment plan was based on a framework (The Heiney-Adams Recruitment Model) that we developed, which combines relationship building and social marketing. We evaluated the success of our model using several different recruitment sources including: mailed letters, physician referral, and self-referral. Recruitment rates ranged from 67% for a support services department mailing to 100% for physician referral. While our original list of contacted patients was comprised of only 13% African American (AA) men, 22% of our recruited participants were AA. One of the strongest barriers to recruitment was strict patient eligibility. Another significant barrier was the lack of electronic records systems to allow for the identification of large numbers of potential participants. In conclusion, our model incorporating social marketing and relationship building was quite successful in recruiting for a prostate cancer behavioral study, particularly AA participants. In developing strategies, future researchers should attend to issues of staffing, financial resources, physician support, and eligibility criteria in the light of study accrual.

  6. Recruitment of older adults to three preventative lifestyle improvement studies.

    Science.gov (United States)

    Chatters, Robin; Newbould, Louise; Sprange, Kirsty; Hind, Daniel; Mountain, Gail; Shortland, Katy; Powell, Lauren; Gossage-Worrall, Rebecca; Chater, Tim; Keetharuth, Anju; Lee, Ellen; Woods, Bob

    2018-02-20

    Recruiting isolated older adults to clinical trials is complex, time-consuming and difficult. Previous studies have suggested querying existing databases to identify appropriate potential participants. We aim to compare recruitment techniques (general practitioner (GP) mail-outs, community engagement and clinician referrals) used in three randomised controlled trial (RCT) studies assessing the feasibility or effectiveness of two preventative interventions in isolated older adults (the Lifestyle Matters and Putting Life In Years interventions). During the three studies (the Lifestyle Matters feasibility study, the Lifestyle Matters RCT, the Putting Life In Years RCT) data were collected about how participants were recruited. The number of letters sent by GP surgeries for each study was recorded. In the Lifestyle Matters RCT, we qualitatively interviewed participants and intervention facilitators at 6 months post randomisation to seek their thoughts on the recruitment process. Referrals were planned to be the main source of recruitment in the Lifestyle Matters feasibility study, but due to a lack of engagement from district nurses, community engagement was the main source of recruitment. District nurse referrals and community engagement were also utilised in the Lifestyle Matters and Putting Life In Years RCTs; both mechanisms yielded few participants. GP mail-outs were the main source of recruitment in both the RCTs, but of those contacted, recruiting yield was low (recruited. Participants recommended that direct contact with health professionals would be the most beneficial way to recruit. Recruitment to the Lifestyle Matters RCT did not mirror recruitment to the feasibility study of the same intervention. Direct district nurse referrals were not effective at recruiting participants. The majority of participants were recruited via GP mail-outs, which may have led to isolated individuals not being recruited to the trials. Further research is required into

  7. Using marketing theory to inform strategies for recruitment: a recruitment optimisation model and the txt2stop experience

    Science.gov (United States)

    2014-01-01

    Background Recruitment is a major challenge for many trials; just over half reach their targets and almost a third resort to grant extensions. The economic and societal implications of this shortcoming are significant. Yet, we have a limited understanding of the processes that increase the probability that recruitment targets will be achieved. Accordingly, there is an urgent need to bring analytical rigour to the task of improving recruitment, thereby increasing the likelihood that trials reach their recruitment targets. This paper presents a conceptual framework that can be used to improve recruitment to clinical trials. Methods Using a case-study approach, we reviewed the range of initiatives that had been undertaken to improve recruitment in the txt2stop trial using qualitative (semi-structured interviews with the principal investigator) and quantitative (recruitment) data analysis. Later, the txt2stop recruitment practices were compared to a previous model of marketing a trial and to key constructs in social marketing theory. Results Post hoc, we developed a recruitment optimisation model to serve as a conceptual framework to improve recruitment to clinical trials. A core premise of the model is that improving recruitment needs to be an iterative, learning process. The model describes three essential activities: i) recruitment phase monitoring, ii) marketing research, and iii) the evaluation of current performance. We describe the initiatives undertaken by the txt2stop trial and the results achieved, as an example of the use of the model. Conclusions Further research should explore the impact of adopting the recruitment optimisation model when applied to other trials. PMID:24886627

  8. Recruitment and selection of candidates in the Republic of Serbia

    OpenAIRE

    Simić, Ivana; Marinović-Matović, Ivana

    2013-01-01

    After a theoretical discussion about recruitment and selection, the key phases of the human resources management process, this paper analyzes the recruitment and selection practices in the Republic of Serbia. These practices, further, are compared with the recruitment and selection practices in certain European and non-European countries. The basis of the mentioned analyses is the data obtained from CRANET research, published in 2011.

  9. Trolling new media: violent extremist groups recruiting through social media

    OpenAIRE

    Chang, Mark D.

    2015-01-01

    Approved for public release; distribution is unlimited With the advent and subsequent growth of several new media technologies, violent extremist groups have incorporated social media into recruiting strategies. How are violent extremist groups using social media for recruiting? This thesis explores several new media technologies—websites, blogs, social media, mobile phones, and online gaming—to determine if violent extremist groups rely on social media for recruiting. By comparing the com...

  10. Stress Fracture of the Proximal Fibula in Military Recruits

    OpenAIRE

    Hong, Seoung Hwan; Chu, In Tak

    2009-01-01

    Background We wanted to report on stress fracture of the proximal fibula and to suggest the pathomechanism of this fracture. Methods Between April 2004 through April 2005, the military recruits who complained of leg pain during the 6 weeks basic training in the Republic of Korea Marine Corps education and training group were evaluated according to their clinical manifestations and plain radiographs. Results Twelve recruits of 635 recruits who complained leg pain were diagnosed as having fibul...

  11. Nurses as participants in research: an evaluation of recruitment techniques.

    Science.gov (United States)

    Luck, Lauretta; Chok, Harrison Ng; Wilkes, Lesley

    2017-09-19

    Recruitment and retention of participants, as well as response rates, can be challenging in nursing research. This can be because of the questions asked; the choice of methodology; the methods used to collect data; the characteristics of potential participants; the sample size required; and the duration of the study. Additionally, conducting research with nurses as participants presents several issues for them, including the time needed to participate in the research, the competing commitments for clinical practice, the political and environmental climate, and recruitment itself. To report on research studies conducted by the authors at a tertiary teaching hospital, to show the lessons learned when recruiting nurses to participate in nursing research. The authors discuss factors that supported recruitment of nurses in these studies, including the use of the personal touch and multiple recruitment strategies in a single study. Videos and photography facilitate interdisciplinary research and can be a valuable means of non-verbal data collection, especially with participants affected by disabilities, and can support research methods, such as the use of questionnaires. Recruiting nurses for research can be challenging. We suggest that researchers consider using more than one recruitment strategy when recruiting nurse participants. Recruitment is more successful if researchers align the aim(s) of the research with nurse's concerns and contexts. ©2012 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

  12. Development of a Test Battery to Select Navy Recruiters

    National Research Council Canada - National Science Library

    Penney, Lisa M; Borman, Walter C; Bearden, Ronald M

    2007-01-01

    .... the students were administered a trial predictor battery while at the school, and performance ratings and production data were collected after participants had been assigned to recruiting duty...

  13. Some Contributions on Personnel Recruitment and Selection for the Administrative Council, the Participative Management Organism of a Public Enterprise

    Directory of Open Access Journals (Sweden)

    Solomia Andres

    2017-12-01

    Full Text Available The paper presents some contributions and analyses of regulations and practice in participative management, realized by a public enterprise from the Caras-Severin District. These ideas represent the beginning of research in this new activity domain, starting from personnel recruitment and selection activities for the participative management organism, which is the Administration Council.

  14. Effects of hydrology on red mangrove recruits

    Science.gov (United States)

    Doyle, Thomas W.

    2003-01-01

    growth of the red mangrove, Rhizophora mangle (fig. 1). Red mangrove propagules (recruits) of select sizes and genotypes (i.e., genetically similar groups) were planted both in greenhouses and in the field. Seedling growth was monitored in both studies on a quarterly basis for over a year; measurements included shoot growth, seedling height, and a final harvest of plant biomass.

  15. Improving Recruiting of the 6th Recruiting Brigade Through Statistical Analysis and Efficiency Measures

    Science.gov (United States)

    2014-12-01

    Joint Chief of Staff General (GEN) Martin E. Dempsey projects that by 2020 “we’re going to need as much diversity and as much talent as we can possibly...Recruiting, Retention Incentives,” American Force Press, March 3, 2009, http://www.defense.gov/news/newsarticle.aspx?id=53310. 8 Bernard Rostker, I Want You...37 Devore, Probability and Statistics, 422. 63 that the null hypothesis 1: 0OP rH P P= = = is rejected for the xP factor, giving grounds to

  16. Improving blood donor recruitment and retention: integrating theoretical advances from social and behavioral science research agendas.

    Science.gov (United States)

    Ferguson, Eamonn; France, Christopher R; Abraham, Charles; Ditto, Blaine; Sheeran, Paschal

    2007-11-01

    Increasing blood donor recruitment and retention is of key importance to transfusion services. Research within the social and behavioral science traditions has adopted separate but complementary approaches to addressing these issues. This article aims to review both of these types of literature, examine theoretical developments, identify commonalities, and offer a means to integrate these within a single intervention approach. The social and behavioral science literature on blood donor recruitment and retention focusing on theory, interventions, and integration is reviewed. The role of emotional regulation (anticipated anxiety and vasovagal reactions) is central to both the behavioral and the social science approaches to enhancing donor motivation, yet although intentions are the best predictor of donor behavior, interventions targeting enactment of intentions have not been used to increase donation. Implementation intentions (that is, if-then plans formed in advance of acting) provide a useful technique to integrate findings from social and behavioral sciences to increase donor recruitment and retention. After reviewing the literature, implementation intention formation is proposed as a technique to integrate the key findings and theories from the behavioral and social science literature on blood donor recruitment and retention.

  17. Telomerase recruitment in Saccharomyces cerevisiae is not dependent on Tel1-mediated phosphorylation of Cdc13.

    Science.gov (United States)

    Gao, Hua; Toro, Tasha B; Paschini, Margherita; Braunstein-Ballew, Bari; Cervantes, Rachel B; Lundblad, Victoria

    2010-12-01

    In Saccharomyces cerevisiae, association between the Est1 telomerase subunit and the telomere-binding protein Cdc13 is essential for telomerase to be recruited to its site of action. A current model proposes that Tel1 binding to telomeres marks them for elongation, as the result of phosphorylation of a proposed S/TQ cluster in the telomerase recruitment domain of Cdc13. However, three observations presented here argue against one key aspect of this model. First, the pattern of Cdc13 phosphatase-sensitive isoforms is not altered by loss of Tel1 function or by mutations introduced into two conserved serines (S249 and S255) in the Cdc13 recruitment domain. Second, an interaction between Cdc13 and Est1, as monitored by a two-hybrid assay, is dependent on S255 but Tel1-independent. Finally, a derivative of Cdc13, cdc13-(S/TQ)11→(S/TA)11, in which every potential consensus phosphorylation site for Tel1 has been eliminated, confers nearly wild-type telomere length. These results are inconsistent with a model in which the Cdc13-Est1 interaction is regulated by Tel1-mediated phosphorylation of the Cdc13 telomerase recruitment domain. We propose an alternative model for the role of Tel1 in telomere homeostasis, which is based on the assumption that Tel1 performs the same molecular task at double-strand breaks (DSBs) and chromosome termini.

  18. Recruiting a young adolescent rural cohort: Costs and lessons learnt

    Directory of Open Access Journals (Sweden)

    Krestina L. Amon

    2016-04-01

    Full Text Available Background: Adolescent recruitment into longitudinal health studies is challenging. The aim of this paper is to report the detailed process and costs of recruiting young adolescents and their families into an intensive longitudinal study of the effects of puberty hormones on health, behaviour and wellbeing in early adolescence, based in regional/rural Australia. Methods: Participants were recruited using a saturation strategy of targeted methods (including school visits and community events and non-targeted recruitment approaches (including print and electronic media advertising, and social media. Direct (face-to-face contact with the public and indirect (behind-the-scenes preparatory activities researcher hours were calculated for each of the recruitment strategies. Results: The study recruited 342 adolescent participants and a parent/guardian over two years. School and community-based recruitment required 6.2 and 6.0 researcher hours per activity, respectively. Direct researcher hours were primarily spent on delivering presentations and connecting with community members at community events. The majority of indirect hours were spent preparing and assembling information packs for distribution to students and parents during school visits. Non-targeted recruitment strategies using media advertising were the most frequently used methods. Researchers were estimated to have spent less than one hour for each media activity. In 27 months, an estimated $250,000 was spent on recruitment activities and resources. A combination of methods was used to recruit young adolescents and their families into a longitudinal health study. Conclusions: The financial costs and researcher time committed to this study highlight the labour-intensive nature of recruitment. The data presented are useful for researchers planning longitudinal studies in adolescents.

  19. Do larval supply and recruitment vary among chemosynthetic environments of the deep sea?

    Directory of Open Access Journals (Sweden)

    Anna Metaxas

    Full Text Available BACKGROUND: The biological communities that inhabit chemosynthetic environments exist in an ephemeral and patchily distributed habitat with unique physicochemical properties that lead to high endemicity. Consequently, the maintenance and recovery from perturbation of the populations in these habitats is, arguably, mainly regulated by larval supply and recruitment. METHODOLOGY/PRINCIPAL FINDINGS: WE USE DATA FROM THE PUBLISHED SCIENTIFIC LITERATURE TO: (1 compare the magnitudes of and variability in larval supply and settlement and recruitment at hydrothermal vents, seeps, and whale, wood and kelp falls; (2 explore factors that affect these life history processes, when information is available; and (3 explore taxonomic affinities in the recruit assemblages of the different chemosynthetic habitats, using multivariate statistical techniques. Larval supply at vents can vary across segments by several orders of magnitude for gastropods; for bivalves, supply is similar at vents on different segments, and at cold seeps. The limited information on larval development suggests that dispersal potential may be highest for molluscs from cold seeps, intermediate for siboglinids at vents and lowest for the whale-bone siboglinid Osedax. Settlement is poorly studied and only at vents and seeps, but tends to be highest near an active source of emanating fluid in both habitats. Rate of recruitment at vents is more variable among studies within a segment than among segments. Across different chemosynthetic habitats, recruitment rate of bivalves is much more variable than that of gastropods and polychaetes. Total recruitment rate ranges only between 0.1 and 1 ind dm(-2 d(-1 across all chemosynthetic habitats, falling above rates in the non-reducing deep sea. The recruit assemblages at vents, seeps and kelp falls have lower taxonomic breadth, and include more families and genera that have many species more closely related to each other than those at whale and wood

  20. TIMP-3 recruits quiescent hematopoietic stem cells into active cell cycle and expands multipotent progenitor pool.

    Science.gov (United States)

    Nakajima, Hideaki; Ito, Miyuki; Smookler, David S; Shibata, Fumi; Fukuchi, Yumi; Morikawa, Yoshihiro; Ikeda, Yuichi; Arai, Fumio; Suda, Toshio; Khokha, Rama; Kitamura, Toshio

    2010-11-25

    Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production. The cycling states of HSCs are regulated by the extracellular factors such as cytokines and extracellular matrix; however, the molecular circuitry for such regulation remains elusive. Here we show that tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous regulator of metalloproteinases, stimulates HSC proliferation by recruiting quiescent HSCs into the cell cycle. Myelosuppression induced TIMP-3 in the bone marrow before hematopoietic recovery. Interestingly, TIMP-3 enhanced proliferation of HSCs and promoted expansion of multipotent progenitors, which was achieved by stimulating cell-cycle entry of quiescent HSCs without compensating their long-term repopulating activity. Surprisingly, this effect did not require metalloproteinase inhibitory activity of TIMP-3 and was possibly mediated through a direct inhibition of angiopoietin-1 signaling, a critical mediator for HSC quiescence. Furthermore, bone marrow recovery from myelosuppression was accelerated by over-expression of TIMP-3, and in turn, impaired in TIMP-3-deficient animals. These results suggest that TIMP-3 may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy or ex vivo expansion of HSCs.

  1. The MSX1 homeoprotein recruits G9a methyltransferase to repressed target genes in myoblast cells.

    Directory of Open Access Journals (Sweden)

    Jingqiang Wang

    Full Text Available Although the significance of lysine modifications of core histones for regulating gene expression is widely appreciated, the mechanisms by which these modifications are incorporated at specific regulatory elements during cellular differentiation remains largely unknown. In our previous studies, we have shown that in developing myoblasts the Msx1 homeoprotein represses gene expression by influencing the modification status of chromatin at its target genes. We now show that genomic binding by Msx1 promotes enrichment of the H3K9me2 mark on repressed target genes via recruitment of G9a histone methyltransferase, the enzyme responsible for catalyzing this histone mark. Interaction of Msx1 with G9a is mediated via the homeodomain and is required for transcriptional repression and regulation of cellular differentiation, as well as enrichment of the H3K9me2 mark in proximity to Msx1 binding sites on repressed target genes in myoblast cells as well as the developing limb. We propose that regulation of chromatin status by Msx1 recruitment of G9a and other histone modifying enzymes to regulatory regions of target genes represents an important means of regulating the gene expression during development.

  2. Evolutionary recruitment of flexible Esrp-dependent splicing programs into diverse embryonic morphogenetic processes.

    Science.gov (United States)

    Burguera, Demian; Marquez, Yamile; Racioppi, Claudia; Permanyer, Jon; Torres-Méndez, Antonio; Esposito, Rosaria; Albuixech-Crespo, Beatriz; Fanlo, Lucía; D'Agostino, Ylenia; Gohr, Andre; Navas-Perez, Enrique; Riesgo, Ana; Cuomo, Claudia; Benvenuto, Giovanna; Christiaen, Lionel A; Martí, Elisa; D'Aniello, Salvatore; Spagnuolo, Antonietta; Ristoratore, Filomena; Arnone, Maria Ina; Garcia-Fernàndez, Jordi; Irimia, Manuel

    2017-11-27

    Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates.

  3. Receptor activity-independent recruitment of βarrestin2 reveals specific signalling modes

    Science.gov (United States)

    Terrillon, Sonia; Bouvier, Michel

    2004-01-01

    The roles of βarrestins in regulating G protein coupling and receptor endocytosis following agonist stimulation of G protein-coupled receptors are well characterised. However, their ability to act on their own as direct modulators or activators of signalling remains poorly characterised. Here, βarrestin2 intrinsic signalling properties were assessed by forcing the recruitment of this accessory protein to vasopressin V1a or V2 receptors independently of agonist-promoted activation of the receptors. Such induction of a stable interaction with βarrestin2 initiated receptor endocytosis leading to intracellular accumulation of the βarrestin/receptor complexes. Interestingly, βarrestin2 association to a single receptor protomer was sufficient to elicit receptor dimer internalisation. In addition to recapitulating βarrestin2 classical actions on receptor trafficking, the receptor activity-independent recruitment of βarrestin2 activated the extracellular signal-regulated kinases. In the latter case, recruitment to the receptor itself was not required since kinase activation could be mediated by βarrestin2 translocation to the plasma membrane in the absence of any interacting receptor. These data demonstrate that βarrestin2 can act as a ‘bonafide' signalling molecule even in the absence of activated receptor. PMID:15385966

  4. A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation.

    Science.gov (United States)

    Zhao, Zhenze; Ma, Xiuye; Hsiao, Tzu-Hung; Lin, Gregory; Kosti, Adam; Yu, Xiaojie; Suresh, Uthra; Chen, Yidong; Tomlinson, Gail E; Pertsemlidis, Alexander; Du, Liqin

    2014-05-15

    Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy.

  5. Modelling the effect of food availability on recruitment success of ...

    African Journals Online (AJOL)

    The results show the importance of food (especially diatoms and copepods) dynamics on the spatial and temporal patterns of recruitment success, and also confirm the importance of the spawning area, timing and water depth on the recruitment success of Cape anchovy larvae. Keywords: 3-D modelling, IBM model, pelagic ...

  6. Physician recruitment and retention in rural and underserved areas.

    Science.gov (United States)

    Lee, Dane M; Nichols, Tommy

    2014-01-01

    The purpose of this paper is to identify the challenges when recruiting and retaining rural physicians and to ascertain methods that make rural physician recruitment and retention successful. There are studies that suggest rural roots is an important factor in recruiting rural physicians, while others look at rural health exposure in medical school curricula, self-actualization, community sense and spousal perspectives in the decision to practice rural medicine. An extensive literature review was performed using Academic Search Complete, PubMed and The Cochrane Collaboration. Key words were rural, rural health, community hospital(s), healthcare, physicians, recruitment, recruiting, retention, retaining, physician(s) and primary care physician(s). Inclusion criteria were peer-reviewed full-text articles written in English, published from 1997 and those limited to USA and Canada. Articles from foreign countries were excluded owing to their unique healthcare systems. While there are numerous articles that call for special measures to recruit and retain physicians in rural areas, there is an overall dearth. This review identifies several articles that suggest recruitment and retention techniques. There is a need for a research agenda that includes valid, reliable and rigorous analysis regarding formulating and implementing these strategies. Rural Americans are under-represented when it comes to healthcare and what research there is to assist recruitment and retention is difficult to find. This paper identify the relevant research and highlights key strategies.

  7. The effects of a wildfire on pine seedling recruitment

    Science.gov (United States)

    Paula C. Gnehm; Brad Hadley

    2007-01-01

    We investigated the effects of a single arson wildfire by comparing its impact on pine seedling recruitment with that of both prescribed fire and unburned compartments. Although a t-test detected no significant difference in pine seedling recruitment (p = 0.38), the "wildfire" treatment produced 127 more seedlings than the unburned...

  8. Analysis and Modeling of U.S. Army Recruiting Markets

    Science.gov (United States)

    2016-03-24

    Share (Source: DMDC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 xi List of Tables Table Page 1 Recruiting Market Segmentation ...collectively called Market and Mission Analysis (MMA). To conduct MMA, USAREC defines each recruiting market in terms of elements and segments . The...enlisted and are awaiting basic combat training; In addition to the market elements, USAREC uses market segments —individuals grouped by like

  9. Personnel Recruitment and Retention Strategies in Lagos State Civil ...

    African Journals Online (AJOL)

    Lagos State Civil Service (LSCS) exists to implement policies of government. To realize this goal, personnel are needed, which are products of personnel recruitment and retention strategies (PR & RSs) of the civil service (CS). This study empirically examined personnel recruitment and retention strategies in LSCS.

  10. Coping by Copying? Higher Education Institutions' Student Recruitment Strategies

    Science.gov (United States)

    Frolich, Nicoline; Brandt, Synnove; Hovdhaugen, Elisabeth; Aamodt, Per Olaf

    2009-01-01

    Growing national and international competition for students puts pressure on higher education institutions (HEIs) to develop marketing and student recruitment strategies; these are also driven by financial stress caused by performance-based funding mechanisms. In this paper we explore Norwegian HEIs' student recruitment strategies. What type of…

  11. Recruiting Experienced Educators: A Model and a Test.

    Science.gov (United States)

    Winter, Paul A.

    1996-01-01

    A model was developed for recruiting experienced educators, extending the recruitment-as-marketing theory. To assess the model's utility, 168 experienced female teachers posed as job applicants responding to position advertisements. Participant reactions were more favorable when advertisements contained intrinsic job attributes, a personal tone,…

  12. Limits to meritocracy? Gender in academic recruitment and promotion processes

    DEFF Research Database (Denmark)

    Nielsen, Mathias Wullum

    2016-01-01

    According to the literature, women researchers are sometimes at a disadvantage in academic recruitment due to insufficient network ties and subtle gender biases among evaluators. But how exactly do highly formal recruitment procedures allow space for mobilizing informal, potentially gendered, net...

  13. Student Recruitment: A Framework developed through A Multi ...

    African Journals Online (AJOL)

    Widening the access to higher education as a response to the global shortage of health care workers necessitates a framework to recruit quality students for professions in the health sciences. The aim is to describe the development of a framework to aid with the recruitment of nursing students, but can also be utilised in the ...

  14. Recruitment and Retention of Latino Children in a Lifestyle Intervention

    Science.gov (United States)

    Guzman, Angelica; Richardson, Irma M.; Gesell, Sabina; Barkin, Shari L.

    2009-01-01

    Objective: To describe promising recruitment and retention strategies for transient Latino populations, assisting investigators who work with this population in their research design and implementation. Methods: Strategies in recruitment and retention from a year-long intervention in children and their families are described. Results: Of the 159…

  15. IDENTIFYING RECRUITMENT AND RETENTION ISSUES FOR THE NATIONAL CHILDREN'S STUDY

    Science.gov (United States)

    Recruitment and Retention Issues for the National Children's StudyDanelle T Lobdell1, Suzanne Gilboa2, Pauline Mendola1 (1US EPA, NHEERL; 2UNC Chapel Hill)A better understanding of the most effective recruitment techniques and retention strategies for longitudinal, co...

  16. LP model for periodic recruitment and retrenchment of manpower in ...

    African Journals Online (AJOL)

    In this paper we have examined the manpower planning problem in which the maximum total number of employees to be recruited when the organization is in full operation is known. The manpower system has no initial employees at period n=0. The system also allows a periodic recruitment and retrenchment for a finite ...

  17. Abundance, recruitment and residency of two sparids in an ...

    African Journals Online (AJOL)

    The recruitment of distinct year-class cohorts in two sparid species, Rhabdosargus holubi and Lithognathus lithognathus, were linked to records of daily mouth state in the intermittently open East Kleinemonde Estuary, South Africa, between 1995 and 2006. L. lithognathus only recruited into the estuary in years when the ...

  18. Facilitating recruitment of patients with schizophrenia to a clinical trial

    DEFF Research Database (Denmark)

    Grønbech, Bettina Ellen; Aagaard, Jørgen; Jensen, Svend Eggert

    People with severe mental illness, such as schizophrenia have higher rates of mortality especially due to cardiovascular disease. We have established a clinical trial named “Coronary artery disease and schizophrenia”. However, patients with schizophrenia have cognitive disturbances, which make re...... recruitment of patients challenging. The purpose of this study is to understand which type of recruitment strategy is needed in clinical trials....

  19. Recruitment barriers for prophylactic vaccine trials: A study in Belgium.

    Science.gov (United States)

    Harrington, Lauriane; Van Damme, Pierre; Vandermeulen, Corinne; Mali, Stéphanie

    2017-12-04

    Recruitment of volunteers is one of the main challenges in clinical trial management, and there is little information about recruitment barriers for preventative vaccine trials. We investigated both the recruitment barriers and recruitment strategies for preventive vaccine trials in Belgium. A 10 min survey was used as well as interviews of staff at all clinical trial sites in Belgium that regularly perform vaccine trials. We observed that there are successful recruitment strategies and few recruitment issues for trials involving healthy adults and those over 65 years old. However, challenges face the recruitment of paediatric populations, pregnant women, patients and the very elderly (over 85 years old). From these results, we identified three priority areas to increase recruitment for prophylactic vaccine trials in Belgium. These are: the lack of public knowledge about infectious diseases; the lack of resources of healthcare professionals to take part in clinical trials; and the burden to potential volunteers to take part in a trial. These were discussed with stakeholders and solutions were proposed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. The Four ‘Ps’ of Hospitality Recruiting

    Directory of Open Access Journals (Sweden)

    John D. Murtha

    2013-07-01

    Full Text Available When recruiting from university programs, there is a consensus among hospitality professionals about the qualities that make candidates achieve success in our industry. These can be categorized as preparation, presentation, purpose, and passion. The Four ‘Ps’ represent a useful assessment system for recruiters, and candidates should be aware that these categories are being considered.

  1. Stock-environment recruitment analysis for Namibian Cape hake ...

    African Journals Online (AJOL)

    Our results are consistent with those of other studies suggesting a significant influence of environmental conditions on recruitment at a low spawning stock level. Our study highlights the importance of assessing the combined non-linear effects of both biotic and abiotic factors on hake recruitment. Keywords: generalised ...

  2. Differential Recruitment of Distinct Amygdalar Nuclei across Appetitive Associative Learning

    Science.gov (United States)

    Cole, Sindy; Powell, Daniel J.; Petrovich, Gorica D.

    2013-01-01

    The amygdala is important for reward-associated learning, but how distinct cell groups within this heterogeneous structure are recruited during appetitive learning is unclear. Here we used Fos induction to map the functional amygdalar circuitry recruited during early and late training sessions of Pavlovian appetitive conditioning. We found that a…

  3. Spatial and temporal variability in recruitment of intertidal mussels ...

    African Journals Online (AJOL)

    IntenSity of intertidal mussel recruitment was compared across a range of different spatial and temporal scales around the coast of southern Africa between June 1995 and October 1996. Comparison of the east and west coasts revealed significantly higher recruit densities on the west coast, corresponding to larger adult ...

  4. This Year, Colleges Recruited Students in a "Hall of Mirrors"

    Science.gov (United States)

    Hoover, Eric; Supiano, Beckie

    2009-01-01

    Admissions deans everywhere shared concerns about recruiting students during a recession as they tried to discern how, or if, the economy would affect demand for their institutions. Amid this uncertainty, colleges used many different strategies. Some recruited more here and less there. Some offered more merit aid, while others scaled back. Some…

  5. Spatial and temporal variability in recruitment of intertidal mussels ...

    African Journals Online (AJOL)

    Intensity of intertidal mussel recruitment was compared across a range of different spatial and temporal scales around the coast of southern Africa between June 1995 and October 1996. Comparison of the east and west coasts revealed significantly higher recruit densities on the west coast, corresponding to larger adult ...

  6. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment.

    Science.gov (United States)

    Vanden Berg-Foels, Wendy S

    2014-02-01

    Tissue engineering uses cells, signaling molecules, and/or biomaterials to regenerate injured or diseased tissues. Ex vivo expanded mesenchymal stem cells (MSC) have long been a cornerstone of regeneration therapies; however, drawbacks that include altered signaling responses and reduced homing capacity have prompted investigation of regeneration based on endogenous MSC recruitment. Recent successful proof-of-concept studies have further motivated endogenous MSC recruitment-based approaches. Stem cell migration is required for morphogenesis and organogenesis during development and for tissue maintenance and injury repair in adults. A biomimetic approach to in situ tissue regeneration by endogenous MSC requires the orchestration of three main stages: MSC recruitment, MSC differentiation, and neotissue maturation. The first stage must result in recruitment of a sufficient number of MSC, capable of effecting regeneration, to the injured or diseased tissue. One of the challenges for engineering endogenous MSC recruitment is the selection of effective chemoattractant(s). The objective of this review is to synthesize and evaluate evidence of recruitment efficacy by reported chemoattractants, including growth factors, chemokines, and other more recently appreciated MSC chemoattractants. The influence of MSC tissue sources, cell culture methods, and the in vitro and in vivo environments is discussed. This growing body of knowledge will serve as a basis for the rational design of regenerative therapies based on endogenous MSC recruitment. Successful endogenous MSC recruitment is the first step of successful tissue regeneration.

  7. Recruitment Pattern Of Macrobrachium vollenhovenii In The Lagos ...

    African Journals Online (AJOL)

    Recruitment pattern of Macrobrachium vollenhovenii in the Lagos – Lekki Lagoon System was estimated from a time series length-frequency data of two years (April 2002 – May 2004). The annual recruitment pattern was estimate through back-projection, along a trajectory defined by the von Bertalanffy Growth Formula ...

  8. Reflecting on e-Recruiting Research Using Grounded Theory

    NARCIS (Netherlands)

    Wolfswinkel, Joost; Furtmueller-Ettinger, Elfriede; Wilderom, Celeste P.M.

    2010-01-01

    This paper presents a systematic review of the e-Recruiting literature through a grounded theory lens. The large number of publications and the increasing diversity of publications on e-Recruiting research, as the most studied area within e-HRM (Electronic Human Resource Management), calls for a

  9. First-Year Seminar Faculty: Recruitment, Supports, Motivators, and Challenges

    Science.gov (United States)

    Sobel, Karen

    2018-01-01

    The majority of universities and four-year colleges in the USA currently offer first-year seminars in at least one format. These programs often pride themselves in recruiting from among their institutions' best teachers to lead the seminars. In reality, this process of recruitment to teach in the program, as well as retention of faculty members…

  10. Academic staff recruitment and retention challenges at the University ...

    African Journals Online (AJOL)

    Publicly available University of Botswana documents about the university's organisational structure, policies, and processes were reviewed. Results. Over a 5-year period, the school recruited 74 academics worldwide; 30 of them left the school. Retention was a greater challenge than recruitment. The school had difficulty ...

  11. Dynamics of recruitment of larval and juvenile Cape stumpnose ...

    African Journals Online (AJOL)

    Recruitment of early life stages into estuaries is an integral part of the life cycle of many marine fish species. Although estuaries are naturally environmentally dynamic, they also are subject to anthropogenic disturbances, including land use and climate change, which may affect recruitment. Rhabdosargus holubi is an ...

  12. Recruitment and quality academic staff selection: the case study of ...

    African Journals Online (AJOL)

    The sources from which organizations decide to select personnel from are central to its ability to survive, adapt, and grow (Noe et al, 2004:171). The paper examines a case study of recruitment and selection of quality academic staff into Covenant University. The paper addresses the factors that could affect recruitment ...

  13. Picking Linebackers or Athletes: Reframing the Risks in Teacher Recruitment

    Science.gov (United States)

    Pomson, Alex

    2010-01-01

    Set in a private parochial high school, this case invites consideration of the costs and benefits in a range of tactics that schools use for teacher recruitment. The case calls attention to the technical solutions that make one particular school an adept recruiter of teachers and to the extensive human and social capital at its disposal. At the…

  14. Effects of river sediments on coral recruitment, algal abundance ...

    African Journals Online (AJOL)

    The effects of sediment concentration and season on coral recruitment algal abundance nd benthic community structure were studied in Kenyan coral reef lagoons to determine their potential influence on coral recovery. Nutrient levels and recruit numbers were higher during the southeast monsoon (SEM) than during the ...

  15. Recruitment and growth patterns of juvenile marine teleosts caught ...

    African Journals Online (AJOL)

    Recruitment is, in general, brought about by the arrival of larvae/juveniles in the plankton, followed by the selection of suitable habitats (Luckhurst &. Luckhurst 1977; Russell, Anderson & Talbot 1977; Sale. 1980). Few data are available on recruitment patterns of teleosts in South African waters. Wallace (1975) gives a brief ...

  16. The Recruitment Problem in Psychiatry: A Critical Commentary

    Science.gov (United States)

    Stampfer, Hans

    2011-01-01

    The continuing shortfall in recruitment to Psychiatry is examined with suggestions for affirmative action. Recruitment may improve in the near future because of the high demand for psychiatrists, the incentives offered, greater competition for other specialties and a pool of international graduates willing to work in Psychiatry. There remains the…

  17. Development of a medical staff recruitment system for teaching ...

    African Journals Online (AJOL)

    Recruitment of staff into teaching hospitals in Nigeria, acts as the first step towards creating competitive strength and strategic advantage for such institutions. However, one of the major problems associated with these institutions in the South Western part of Nigeria is their mode of staff recruitment. In this research paper, we ...

  18. Importing Educators: Causes and Consequences of International Teacher Recruitment

    Science.gov (United States)

    American Federation of Teachers (NJ), 2009

    2009-01-01

    This report contains case studies of international recruiters who help school districts in the United States acquire work visas and hire noncitizens. Recruiters sometimes use fees charged to workers to pay for U.S. school officials' overseas trips, where they stay in luxury hotels and handpick teachers at job fairs. Not surprisingly, some school…

  19. Group Seeks Standards for Paid Recruiters of Students

    Science.gov (United States)

    McMurtrie, Beth

    2008-01-01

    In the world of international education, few subjects are as controversial as the use of paid recruiting agents. Paying the agents, particularly on commission, is often viewed as unseemly, if not downright unethical. But a new organization, the American International Recruitment Council, hopes to change that attitude. The council wants to develop…

  20. Recruiting Source Effects: A Test of Two Alternative Explanations.

    Science.gov (United States)

    Breaugh, James A.; Mann, Rebecca B.

    The source of employee recruitment has been related to numerous important work outcomes (e.g., turnover, performance), but reasons for this relationship are not known. To test the viability of two possible explanations for recruiting source effects, i.e., employee level of realistic expectation, or individual differences, information was gathered…

  1. Market, Regulation, Market, Regulation

    DEFF Research Database (Denmark)

    Frankel, Christian; Galland, Jean-Pierre

    2015-01-01

    This paper focuses on the European Regulatory system which was settled both for opening the Single Market for products and ensuring the consumers' safety. It claims that the New Approach and Standardization, and the Global Approach to conformity assessment, which suppressed the last technical...... barriers to trade in Europe, realized the free movement of products by organizing progressively several orders of markets and regulation. Based on historical and institutional documents, on technical publications, and on interviews, this article relates how the European Commission and the Member States had...... alternatively recourse to markets and to regulations, at the three main levels of the New Approach Directives implementation. The article focuses also more specifically on the Medical Devices sector, not only because this New Approach sector has long been controversial in Europe, and has recently been concerned...

  2. Chemical compounds of the foraging recruitment pheromone in bumblebees

    Science.gov (United States)

    Granero, Angeles Mena; Sanz, José M. Guerra; Gonzalez, Francisco J. Egea; Vidal, José L. Martinez; Dornhaus, Anna; Ghani, Junaid; Serrano, Ana Roldán; Chittka, Lars

    2005-08-01

    When the frenzied and irregular food-recruitment dances of bumblebees were first discovered, it was thought that they might represent an evolutionary prototype to the honeybee waggle dance. It later emerged that the primary function of the bumblebee dance was the distribution of an alerting pheromone. Here, we identify the chemical compounds of the bumblebee recruitment pheromone and their behaviour effects. The presence of two monoterpenes and one sesquiterpene (eucalyptol, ocimene and farnesol) in the nest airspace and in the tergal glands increases strongly during foraging. Of these, eucalyptol has the strongest recruitment effect when a bee nest is experimentally exposed to it. Since honeybees use terpenes for marking food sources rather than recruiting foragers inside the nest, this suggests independent evolutionary roots of food recruitment in these two groups of bees.

  3. Recruiting Transcultural Qualitative Research Participants: A Conceptual Model

    Directory of Open Access Journals (Sweden)

    Phyllis Eide

    2005-06-01

    Full Text Available Working with diverse populations poses many challenges to the qualitative researcher who is a member of the dominant culture. Traditional methods of recruitment and selection (such as flyers and advertisements are often unproductive, leading to missed contributions from potential participants who were not recruited and researcher frustration. In this article, the authors explore recruitment issues related to the concept of personal knowing based on experiences with Aboriginal Hawai'ian and Micronesian populations, wherein knowing and being known are crucial to successful recruitment of participants. They present a conceptual model that incorporates key concepts of knowing the other, cultural context, and trust to guide other qualitative transcultural researchers. They also describe challenges, implications, and concrete suggestions for recruitment of participants.

  4. IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Serkan I. Göktuna

    2014-06-01

    Full Text Available The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC therapy.

  5. Resilience Among Naval Recruits: A Quantitative and Qualitative Analysis of Interventions at Recruit Training Command and Implications on Fleet Readiness

    Science.gov (United States)

    2016-03-01

    Positive Self -Talk Exercises ..............................41 2. Intervention 2: Division Discussions ..........................................43 3...organization and serve as sources of self - esteem and identity (Sluss & Ashforth, 2007). Each recruit serves a unique role in their division, whether formal...structured recruit conversations. 1. Intervention 1: Positive Self -Talk Exercises Individual level resilience, as discussed previously, combines both

  6. Ecological drivers of guanaco recruitment: variable carrying capacity and density dependence.

    Science.gov (United States)

    Marino, Andrea; Pascual, Miguel; Baldi, Ricardo

    2014-08-01

    Ungulates living in predator-free reserves offer the opportunity to study the influence of food limitation on population dynamics without the potentially confounding effects of top-down regulation or livestock competition. We assessed the influence of relative forage availability and population density on guanaco recruitment in two predator-free reserves in eastern Patagonia, with contrasting scenarios of population density. We also explored the relative contribution of the observed recruitment to population growth using a deterministic linear model to test the assumption that the studied populations were closed units. The observed densities increased twice as fast as our theoretical populations, indicating that marked immigration has taken place during the recovery phase experienced by both populations, thus we rejected the closed-population assumption. Regarding the factors driving variation in recruitment, in the low- to medium-density setting, we found a positive linear relationship between recruitment and surrogates of annual primary production, whereas no density dependence was detected. In contrast, in the high-density scenario, both annual primary production and population density showed marked effects, indicating a positive relationship between recruitment and per capita food availability above a food-limitation threshold. Our results support the idea that environmental carrying capacity fluctuates in response to climatic variation, and that these fluctuations have relevant consequences for herbivore dynamics, such as amplifying density dependence in drier years. We conclude that including the coupling between environmental variability in resources and density dependence is crucial to model ungulate population dynamics; to overlook temporal changes in carrying capacity may even mask density dependence as well as other important processes.

  7. Participant Outcomes from Methods of Recruitment for Videogame Research.

    Science.gov (United States)

    Ryan, Courtney; Dadabhoy, Hafza; Baranowski, Tom

    2018-02-01

    The most productive methods of recruitment for a videogame for health (G4H) trial are not known. Success or failure of recruitment methods has been reported for a variety of clinical trials, but few specifically for G4H trials. This study's goal was to recruit 444 overweight or obese (body mass index percentile between the 84.5th-99.4th percentiles) children between the ages of 10-12 years. The article reports the results of different methods of participant recruitment. Participants had to agree to three fasting blood samples (baseline, immediately after, and 2 months later); be willing to wear an accelerometer for 7 days at each assessment; read and speak English fluently (because the games were in English); have no history of any condition that would affect what he/she could eat or how much physical activity he/she could get; and have an eligible home computer purchased in the last 5 years with high-speed internet. Hardware criteria reflected the types of computers upon which Diab-Nano could be effectively played. Recruitment was conducted over a 35-month period and included electronic media, print advertising, community recruitment, and an internal volunteer list. Respondents were guided to a web-based screening questionnaire that asked for source of hearing about the study. Although diverse recruitment methods were used, slow recruitment resulted in obtaining only 45% of the recruitment goal (n = 199). Electronic media (e.g., radio, television, and internet), which reached millions of targeted parents, resulted in only 76 respondents, of whom 13 became participants; print media (e.g., magazine, newsletter/newspaper, and mail), which also reached large numbers of parents, resulted in 192 respondents, of whom 19 became participants; community recruitment (e.g., school, friend or family, doctors office, flyer, work, community program) resulted in 162 respondents, of whom 38 became participants; and the internal volunteer list resulted in 413 respondents, of

  8. Real-time images of tidal recruitment using lung ultrasound.

    Science.gov (United States)

    Tusman, Gerardo; Acosta, Cecilia M; Nicola, Marco; Esperatti, Mariano; Bohm, Stephan H; Suarez-Sipmann, Fernando

    2015-12-01

    Ventilator-induced lung injury is a form of mechanical damage leading to a pulmonary inflammatory response related to the use of mechanical ventilation enhanced by the presence of atelectasis. One proposed mechanism of this injury is the repetitive opening and closing of collapsed alveoli and small airways within these atelectatic areas-a phenomenon called tidal recruitment. The presence of tidal recruitment is difficult to detect, even with high-resolution images of the lungs like CT scan. The purpose of this article is to give evidence of tidal recruitment by lung ultrasound. A standard lung ultrasound inspection detected lung zones of atelectasis in mechanically ventilated patients. With a linear probe placed in the intercostal oblique position. We observed tidal recruitment within atelectasis as an improvement in aeration at the end of inspiration followed by the re-collapse at the end of expiration. This mechanism disappeared after the performance of a lung recruitment maneuver. Lung ultrasound was helpful in detecting the presence of atelectasis and tidal recruitment and in confirming their resolution after a lung recruitment maneuver.

  9. Recruitment process of a Chinese immigrant study in Canada.

    Science.gov (United States)

    Zou, Ping

    2017-08-01

    The objectives of this article were to provide a comprehensive overview of the recruitment experience and participant characteristics in an antihypertensive dietary educational intervention pilot trial among Chinese Canadians. The recruitment was conducted in a community centre. Two recruitment approaches, self-referral and proactive recruitment, were used. Among 618 Chinese Canadians in the blood pressure screening, 105 (17.0%) individuals were eligible to participate in this trial. Of the 105 eligible individuals, 45 (42.9%) declined enrollment and 60 (57.1%) consented to participate in the trial and were recruited. The most common reason for refusal was being unable to access to the education location (n=19, 42.2%) followed by being too busy to participate (n=18, 40.0%). All participants were Chinese immigrants and the mean number of years living in Canada was 9.2. Most participants had low English proficiency, accepted Chinese culture more than Western culture, and had strong traditional health beliefs. It is concluded that both self-referral and proactive recruitment approaches were effective. Home-based interventions using Internet and telephone should be used as alternative delivery approaches to improve recruitment rate and facilitate participation. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. A house divided: cooperative and competitive recruitment in vital industries.

    Science.gov (United States)

    Willis, William K; Muslin, Ivan; Timko, Karlyn N

    2016-03-01

    To propose a theoretical based model approach to address the nursing shortage problem of recruiting qualified applicants. Vital industries such as nursing and trucking face a large labour shortage. A literature review focusing on recruitment and realistic job previews examines relevant theories and an indication of the focus of similar research. Game theory illustrates cooperative and competitive recruitment strategies in vital industries. Proposition and model development where cooperative or competitive strategies for recruitment can either increase or decrease the employee applicant pool. Institutional theory states that firms within a population become isomorphic in nature. Firms employing cooperative or competitive strategies for recruitment can change organisational practices through isomorphic processes. Industries facing a labour market shortage using cooperative strategy will use realistic job previews accurately to disseminate information about industry jobs. Realistic job previews will increase the applicant pool through individuals self-selecting into, rather than out of, the applicant pool. Recruitment in the nursing industry has been examined at the individual applicant and organisational level, yet the overall industry has been ignored. As nursing shortages continue, viewing recruitment at the macro level (the overall industry) is appropriate. Game theory as proposed provides opportunities for current research at the industry level. © 2015 John Wiley & Sons Ltd.

  11. Recruitment for Competencies in Public and Private Sectors

    Directory of Open Access Journals (Sweden)

    Codruța OSOIAN

    2014-02-01

    Full Text Available The capacity to attract highly skilled human resources is dependent on the employee recruitment process implemented by organizations, which plays an important role for their competitiveness on the market. As the concern for the success of the recruitment process in public sectors is becoming more salient, the present study compares the use of recruitment practices in public and private sectors through a survey applied to 97 organizations. It also explores the outcomes in terms of quantity and quality of applications received when using various recruitment methods. Common points and differences were identified. Internal recruitment methods and e-recruitment based on job posting on the website of the organization are favored regardless of the type of organization (private or public. The differences weight mostly against public sector as public institutions use less often the recommendations received from acquaintances and networks, post fewer job adds on specialized online job boards, get fewer direct applications from candidates, and participate less often in job fairs. The largest number of applications is received through the use of online job boards, job posting on the website of the hiring organization and job advertising in written press. On the other hand, internal recruitment is perceived to result in attracting the highest quality applications.  

  12. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements

    DEFF Research Database (Denmark)

    Grøntved, Lars; John, Sam; Baek, Songjoon

    2013-01-01

    -binding sites are occupied by C/EBPβ. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPβ for GR recruitment. Disruption of C/EBPβ binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin...... remodelling specifically at sites co-occupied by GR and C/EBPβ. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPβ regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell...

  13. Researchers' perspectives on pediatric obesity research participant recruitment.

    Science.gov (United States)

    Parikh, Yasha; Mason, Maryann; Williams, Karen

    2016-12-01

    Childhood obesity prevalence has tripled over the last three decades. Pediatric obesity has important implications for both adult health as well as the United States economy. In order to combat pediatric obesity, exploratory studies are necessary to create effective interventions. Recruitment is an essential part of any study, and it has been challenging for all studies, especially pediatric obesity studies. The objective of this study was to understand barriers to pediatric obesity study recruitment and review facilitators to overcome recruitment difficulties. Twenty four childhood obesity researchers were contacted. Complete data for 11 researchers were obtained. Interviews were transcribed and analyzed using content analysis. Grounded Theory methodological approach was used, as this was an exploratory study. Investigators YP and MM coded the interviews using 28 codes. Barriers to recruitment included: family and study logistics, family economics, lack of provider interest, invasive protocols, stigma, time restraints of clinicians, lack of patient motivation/interest, groupthink of students in a classroom, and participants who do not accept his or her own weight status. Facilitators to enhance recruitment practices included accommodating participants outside of regular clinic hours, incentivizing participants, cultivating relationships with communities, schools and clinics prior to study recruitment, emphasizing benefits of a study for the patient, and shifting language to focus on health rather than obesity. Pediatric obesity researchers face many standard and some unique challenges to recruitment, reflecting challenges common to clinical research as well as some specific to pediatrics and some specific to obesity research. Both pediatric studies as well as obesity studies are an added challenge to the already-difficult task of general study recruitment. Our findings can be used to make researchers more aware of potential difficulties, approaches and on

  14. Challenges of research recruitment in a university setting in England.

    Science.gov (United States)

    Vadeboncoeur, Claudia; Foster, Charlie; Townsend, Nick

    2017-05-20

    The recruitment is an integral part of most research projects in medical sciences involving human participants. In health promotion research, there is increasing work on the impact of environments. Settings represent environments such as schools where social, physical and psychological development unfolds. In this study, we investigated weight gain in students within a university setting. Barriers to access and recruitment of university students within a specific setting, in the context of health research are discussed. An online survey on health behaviours of first year students across 101 universities in England was developed. Ethics committees of each institutions were contacted to obtain permission to recruit and access their students. Recruitment adverts were standardized and distributed within restrictions imposed by universities. Three time points and incentives were used. Several challenges in recruiting from a university setting were found. These included (i) ethics approval, (ii) recruitment approval, (iii) navigating restrictions on advertisement and (iv) logistics of varying university academic calendars. We also faced challenges of online surveys including low recruitment, retention and low eligibility of respondents. From the 101 universities, 28 allowed dissemination of adverts. We obtained 1026 responses at T1, 599 at T2 and 497 at T3. The complete-case sample represented 13% of those originally recruited at T1. Conducting research on students within the university setting is a time consuming and challenging task. To improve research-based health promotion, universities could work together to increase consistency as to their policies on student recruitment. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Recruitment and retention of home support workers in rural communities.

    Science.gov (United States)

    Sharman, Zena

    2014-01-01

    This qualitative study examined recruitment and retention of home support workers (HSWs) providing home support in rural communities. Thirty-two participants were recruited across four island-based communities located in British Columbia, Canada. Thematic analysis of interview data revealed several key themes: (a) how the rural context shapes HSWs' employment decisions and opportunities; (b) why people become (and stay) HSWs in rural communities; and (c) how rurality influences the nature and scope of HSWs' work. These findings suggest that health human resource policies and programs aimed at HSW recruitment and retention should be tailored to characteristics, strengths, and challenges of rural communities.

  16. Risks of moral exploitation of soldiers through unrealistic recruitment

    OpenAIRE

    Jockheck, Stephan

    2017-01-01

    Not unlike the recent report Filling the ranks on the recruitment problems of the British Army shows for the UK, the German armed forces (Bundeswehr) struggle badly to meet their recruitment goals and to fulfill the “Trendwende Personal” (the turnaround in the personnel strength) as proclaimed by the German Defence Minister Ursula von der Leyen. Last year the recruitment department of the Bundeswehr tried a new way of targeting especially young people on YouTube. With a series of 59 episodes ...

  17. [Drug consumption of armed forces recruits (author's transl)].

    Science.gov (United States)

    Schenk, J

    1980-08-22

    Requestioning of armed forces recruits showed partial increase of their drug consumption while in the army. The consumption of alcoholic beverages as well as cannabis increased, the level of cigaret smoking remained constant. To some extent, the recruits evaluate these changes incorrectly, since they do not always coincide with their intentions with regard to consumption. Alcohol consumption correlates with the situation as experienced by the troops. The Bundeswehr can be held only partially responsible for the heavy drinking since the recruits enter the army already having distinct drinking habits.

  18. Institutional Context and E-recruitment Practices of Danish Organisations

    DEFF Research Database (Denmark)

    Holm, Anna B.

    2014-01-01

    from functional and social pressures of the wider society, such as the labour market and the penetration of the Internet into Danish society. That is reflected in the widespread use of digital HRM in general, and e-recruitment in particular. The study concludes that the recruitment field has...... on interpretive methods and the inductive analysis of data. The data were collected from a number of sources, such as exploratory interviews, observations, websites and other secondary material from 2008-2013. Findings - The findings indicate that recruitment practices are strongly influenced by changes stemming...

  19. A process to manage recruitment to multiple competing studies.

    Science.gov (United States)

    Carpenter, Janet S; Ziner, Kim

    2008-06-01

    Although strategies for decreasing barriers to research participation have been previously published, specific strategies for managing recruitment in the context of multiple, competing studies have not been addressed. This article addresses the development and implementation of a coordinated recruitment core aimed at managing recruitment to multiple studies competing for patients within a breast cancer clinic. The discussion centers around the process used to define the problem and need for change, the proposed change, steps in implementing the change, strategies to facilitate implementation of the change, and initial evaluation, including expected and unexpected benefits. Also included is a discussion of future directions.

  20. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting.

    Science.gov (United States)

    Wu, Shwu-Yuan; Lee, A-Young; Lai, Hsien-Tsung; Zhang, Hong; Chiang, Cheng-Ming

    2013-03-07

    Bromodomain-containing protein 4 (Brd4) is an epigenetic reader and transcriptional regulator recently identified as a cancer therapeutic target for acute myeloid leukemia, multiple myeloma, and Burkitt's lymphoma. Although chromatin targeting is a crucial function of Brd4, there is little understanding of how bromodomains that bind acetylated histones are regulated, nor how the gene-specific activity of Brd4 is determined. Via interaction screen and domain mapping, we identified p53 as a functional partner of Brd4. Interestingly, Brd4 association with p53 is modulated by casein kinase II (CK2)-mediated phosphorylation of a conserved acidic region in Brd4 that selectively contacts either a juxtaposed bromodomain or an adjacent basic region to dictate the ability of Brd4 binding to chromatin and also the recruitment of p53 to regulated promoters. The unmasking of bromodomains and activator recruitment, concurrently triggered by the CK2 phospho switch, provide an intriguing mechanism for gene-specific targeting by a universal epigenetic reader. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Fast and flexible: argentine ants recruit from nearby trails.

    Directory of Open Access Journals (Sweden)

    Tatiana P Flanagan

    Full Text Available Argentine ants (Linepithema humile live in groups of nests connected by trails to each other and to stable food sources. In a field study, we investigated whether some ants recruit directly from established, persistent trails to food sources, thus accelerating food collection. Our results indicate that Argentine ants recruit nestmates to food directly from persistent trails, and that the exponential increase in the arrival rate of ants at baits is faster than would be possible if recruited ants traveled from distant nests. Once ants find a new food source, they walk back and forth between the bait and sometimes share food by trophallaxis with nestmates on the trail. Recruiting ants from nearby persistent trails creates a dynamic circuit, like those found in other distributed systems, which facilitates a quick response to changes in available resources.

  2. Successful Student Recruitment Using Direct Marketing and Information Technology.

    Science.gov (United States)

    Merante, Joseph A.

    1982-01-01

    Educational marketing--which uses marketing methods unique to education institutions, including segmentation, direct mail, and information technology--is discussed. A model for student recruitment developed by the University of Pittsburgh is described. (Author/MLW)

  3. Australian army recruits in training display symptoms of overtraining.

    Science.gov (United States)

    Booth, Christine K; Probert, Bianka; Forbes-Ewan, Chris; Coad, Ross A

    2006-11-01

    The proposition that the demands of recruit training, including physical and psychological stresses, result in symptoms of overtraining was investigated during the 45-day Army Common Recruit Training course. Body mass, physical fitness, fasting blood measures of immune status, hormones (serum free testosterone/cortisol ratio), inflammation, and iron status were measured at baseline and after weeks 5 and 6. Psychological measures of mood and fatigue and general health were measured at the end of each week. Sleep diaries were completed each evening and morning. Evidence for overtraining symptoms of fatigue, sleep disturbance, immune suppression, reduced iron status, high rates of minor injuries, and hormonal changes was found. However, recruits were not pushed so hard that physical performance deteriorated greatly. Accumulated sleep deprivation might be a major contributor to the adverse hormonal changes. We conclude that there was some evidence of recruits being overtrained.

  4. Recruitment and Employment of the Water Pollution Control Specialist.

    Science.gov (United States)

    Sherrard, J. H.; Sherrard, F. A.

    1979-01-01

    Presented are the basic principles of personnel recruitment and employment for the water pollution control field. Attention is given to determination of staffing requirements, effective planning, labor sources, affirmative action, and staffing policies. (CS)

  5. The Importance of Recruitment in the 1990's.

    Science.gov (United States)

    Hutchinson, George

    1988-01-01

    A discussion of the difficulties of enrollment projection examines the wide range of variables affecting enrollments and the likely technological, scientific, manpower, social, and humanistic needs of the world in 2000 that should motivate recruitment efforts. (MSE)

  6. RAND Research Brief: Military Recruiting: Trends, Outlook, and Implications

    National Research Council Canada - National Science Library

    2001-01-01

    ...., those who score well on written aptitude exams and have high school diplomas). Recruiting resources had been cut after the Gulf War, and reports circulated that youth had less interest in joining the military...

  7. Questionnaire survey on recruitment for Japanese Neurology Society.

    Science.gov (United States)

    Nishiyama, Kazutoshi; Amano, Takahiro; Aoki, Masashi; Inuzuka, Takashi; Taniwaki, Takayuki; Toyoshima, Itaru; Hashimoto, Yoichiro; Fukutake, Toshio; Yoshii, Fumihito; Ando, Yukio

    2016-12-28

    Many claim that they do not have enough neurologists in Japan, but supply and demand of neurologists remains to be analyzed. To investigate the recruitment for the Japanese Society of Neurology (JSN), the subcommittee of JSN for education performed a questionnaire-based survey in 80 medical universities and 271 board-certified education facilities throughout Japan. The response rate to the questionnaire was 77.5% in medical universities and 42.4% in education facilities. It was shown that each department of neurology in university recruits average 2.2 doctors, while they supposed that more than 4 doctors to be recruited every year. The questionnaire survey included what measures JSN should take in order to promote recruitment for JSN.

  8. Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies

    NARCIS (Netherlands)

    Schipper-Krom, Sabine; Juenemann, Katrin; Jansen, Anne H.; Wiemhoefer, Anne; van den Nieuwendijk, Rianne; Smith, Donna L.; Hink, Mark A.; Bates, Gillian P.; Overkleeft, Hermen; Ovaa, Huib; Reits, Eric

    2014-01-01

    Neurodegenerative disorders such as Huntington's disease are hallmarked by neuronal intracellular inclusion body formation. Whether proteasomes are irreversibly recruited into inclusion bodies in these protein misfolding disorders is a controversial subject. In addition, it has been proposed that

  9. Family caregiver recruitment via social media: challenges, opportunities and lessons.

    Science.gov (United States)

    Hansen, Dana; Sheehan, Denice K; Stephenson, Pam

    2017-02-02

    Illness blogs are a way seriously ill people communicate publicly about their illness journey. As communication about serious illness increases on social media, it is important to evaluate how this affects the family caregiver. However, identifying and accessing family caregivers remains challenging, especially via social media. The aim of this article is to report the opportunities, challenges and lessons learned from using social media to recruit family caregivers. Recruitment methods included posting study invitations on illness blogs, advertising through Facebook and placing study fliers in the community. Using social media to recruit was inexpensive and provided a wide geographical reach. One important finding was discovering the importance of using language in the recruitment materials that family caregivers could identify with to help deem themselves as eligible to participate in the study.

  10. Beyond traditional advertisements: leveraging Facebook's social structures for research recruitment.

    Science.gov (United States)

    Valdez, Rupa S; Guterbock, Thomas M; Thompson, Morgan J; Reilly, Jeremiah D; Menefee, Hannah K; Bennici, Maria S; Williams, Ishan C; Rexrode, Deborah L

    2014-10-27

    Obtaining access to a demographically and geographically diverse sample for health-related research can be costly and time consuming. Previous studies have reported mixed results regarding the potential of using social media-based advertisements to overcome these challenges. Our aim was to develop and assess the feasibility, benefits, and challenges of recruiting for research studies related to consumer health information technology (IT) by leveraging the social structures embedded in the social networking platform, Facebook. Two recruitment strategies that involved direct communication with existing Facebook groups and pages were developed and implemented in two distinct populations. The first recruitment strategy involved posting a survey link directly to consenting groups and pages and was used to recruit Filipino-Americans to a study assessing the perceptions, use of, and preferences for consumer health IT. This study took place between August and December 2013. The second recruitment strategy targeted individuals with type 2 diabetes and involved creating a study-related Facebook group and asking administrators of other groups and pages to publicize our group to their members. Group members were then directly invited to participate in an online pre-study survey. This portion of a larger study to understand existing health management practices as a foundation for consumer health IT design took place between May and June 2014. In executing both recruitment strategies, efforts were made to establish trust and transparency. Recruitment rate, cost, content of interaction, and characteristics of the sample obtained were used to assess the recruitment methods. The two recruitment methods yielded 87 and 79 complete responses, respectively. The first recruitment method yielded a rate of study completion proportionate to that of the rate of posts made, whereas recruitment successes of the second recruitment method seemed to follow directly from the actions of a subset

  11. Academic staff recruitment and retention challenges at the University ...

    African Journals Online (AJOL)

    year period ending in December 2013. The university's organisational structure, relevant policies, proce- dures and leadership movements are described for their perceived or potential effect on recruitment and retention.[8,16-19] The article.

  12. Soldier's Expectancies, Implications for Recruitment and Job Satisfaction

    National Research Council Canada - National Science Library

    Gelooven, Renier

    1999-01-01

    .... Also expectancies about a job influence attrition and job satisfaction. This paper uses results of several studies to describe the image of the soldiers job and its effects on recruitment, early attrition and job satisfaction.

  13. Mechanism of Archaeal MCM Helicase Recruitment to DNA Replication Origins

    Science.gov (United States)

    Samson, Rachel Y.; Abeyrathne, Priyanka D.; Bell, Stephen D.

    2015-01-01

    Summary Cellular DNA replication origins direct the recruitment of replicative helicases via the action of initiator proteins belonging to the AAA+ superfamily of ATPases. Archaea have a simplified subset of the eukaryotic DNA replication machinery proteins and possess initiators that appear ancestral to both eukaryotic Orc1 and Cdc6. We have reconstituted origin-dependent recruitment of the homohexameric archaeal MCM in vitro with purified recombinant proteins. Using this system, we reveal that archaeal Orc1-1 fulfills both Orc1 and Cdc6 functions by binding to a replication origin and directly recruiting MCM helicase. We identify the interaction interface between these proteins and reveal how ATP binding by Orc1-1 modulates recruitment of MCM. Additionally, we provide evidence that an open-ring form of the archaeal MCM homohexamer is loaded at origins. PMID:26725007

  14. Intersectionality, Recruitment and Selection : Ethnic Minority Candidates in Dutch Parties

    NARCIS (Netherlands)

    Mügge, L.M.

    2016-01-01

    This article aims to contribute to explanations why ethnic minority women outnumber ethnic minority men in national parliaments of European immigration countries. Extending the intersectional lens it asks: which ethnic minority candidates are recruited and selected? Drawing on nine elections

  15. Racial athletic stereotype confirmation in college football recruiting.

    Science.gov (United States)

    Thomas, Grant; Good, Jessica J; Gross, Alexi R

    2015-01-01

    The present study tested real-world racial stereotype use in the context of college athletic recruiting. Stereotype confirmation suggests that observers use stereotypes as hypotheses and interpret relevant evidence in a biased way that confirms their stereotypes. Shifting standards suggest that the evaluative standard to which we hold a target changes as a function of their group membership. We examined whether stereotype confirmation and shifting standards effects would be seen in college football coaches during recruiting. College football coaches evaluated a Black or White player on several attributes and made both zero- and non-zero-sum allocations. Results suggested that coaches used the evidence presented to develop biased subjective evaluations of the players based on race while still maintaining equivalent objective evaluations. Coaches also allocated greater overall resources to the Black recruit than the White recruit.

  16. Demographic processes limiting seedling recruitment in arid grassland restoration

    Science.gov (United States)

    Jeremy J. James; Tony J. Svejcar; Matthew J. Rinella

    2011-01-01

    Seeding is an important management tool in aridland restoration, but seeded species often fail to establish. Previous research has largely focused on the technical aspects of seeding with little effort directed at identifying demographic processes driving recruitment failures.

  17. Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.

    Directory of Open Access Journals (Sweden)

    Samantha P Tull

    2009-08-01

    Full Text Available Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA, arachidonic acid, into the eicosanoid prostaglandin-D(2 (PGD(2 by cyclooxygenase (COX enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA, was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3. This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2 receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2 signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not

  18. Strategies for increasing recruitment to randomised controlled trials: systematic review.

    Directory of Open Access Journals (Sweden)

    Patrina H Y Caldwell

    Full Text Available BACKGROUND: Recruitment of participants into randomised controlled trials (RCTs is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs. METHODS AND FINDINGS: A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies, recruiter differences (eight studies, incentives (two studies, and provision of trial information (19 studies. Strategies that increased people's awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR 1.48, 95% confidence interval (CI 1.00-2.18], attendance at an education session [RR 1.14, 95% CI 1.01-1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14-1.66], or a video about the health condition (RR 1.75, 95% CI 1.11-2.74, and also monetary incentives (RR1.39, 95% CI 1.13-1.64 to RR 1.53, 95% CI 1.28-1.84 improved recruitment. Increasing patients' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study's main limitation was the necessity of

  19. Emotional intelligence and its role in recruitment of nursing students

    OpenAIRE

    Lyon, Steve; Trotter, Fiona; Holt, Barrie; Powell, Elaine; Roe, Andrew

    2013-01-01

    This article considers the concept of emotional intelligence and how it can be used in the recruitment and development of nursing students. The links between emotional intelligence and the qualities of compassion and caring are examined. The ethical difficulties surrounding the use of emotional intelligence tests are explored and the value of using a variety of recruitment methods is emphasised. The article suggests that emotional intelligence is an ability which may be developed through nurs...

  20. Use of social networking for dental hygiene program recruitment.

    Science.gov (United States)

    Ennis, Rachel S

    2011-01-01

    Social networking has become a popular and effective means of communication used by students in the millennial generation. Academic admissions officers are beginning to utilize social networking methods for recruitment of students. However, the dental hygiene literature has reported little information about the use of social networking for recruitment strategies. This paper describes one institutions' process of creating and implementing a social network site for prospective and current students.

  1. Development of the Recruitment Services Market in Ukraine

    OpenAIRE

    Pysarevska Hanna I.

    2013-01-01

    The article analyses tendencies of development of the recruitment services market in Ukraine. It justifies actuality of the study of the recruitment services market, which confirms high and stable demand on the services of personnel agencies. It determines main problems in this sphere: insufficiently high quality of services, absence of professional standards, high fluctuation of personnel in agencies, low qualification of consultants on personnel selection, absence of statistical data about ...

  2. Recruiting an Internet Panel Using Respondent-Driven Sampling

    Directory of Open Access Journals (Sweden)

    Schonlau Matthias

    2014-06-01

    Full Text Available Respondent-driven sampling (RDS is a network sampling technique typically employed for hard-to-reach populations when traditional sampling approaches are not feasible (e.g., homeless or do not work well (e.g., people with HIV. In RDS, seed respondents recruit additional respondents from their network of friends. The recruiting process repeats iteratively, thereby forming long referral chains.

  3. Recruitment and retention of scholarship recipient nursing students and staff.

    Science.gov (United States)

    Tucker, Susan K; Sherrod, Roy A

    2011-12-13

    Few problems are more relevant in health care today than nurse recruitment and retention. The purpose of this study was to identify job satisfaction factors for nurse and nursing student education scholarship recipients, as well as examine the relationship of these factors to the intent to complete contractual agreements. Findings revealed that job satisfaction and a positive image of nursing were influential factors in intent to complete contractual agreements. Results may prove valuable information to recruit nursing students and increase job satisfaction.

  4. Exploring recruitment and selection trends in the Eastern Cape

    Directory of Open Access Journals (Sweden)

    Gerrit J. Louw

    2013-08-01

    Full Text Available Orientation: The recruitment, selection and development of suitable candidates are crucial strategic functions to ensure the competitiveness of corporate and public sector organisations. Research purpose: The purpose of the study was to determine whether targeted organisations have a clear recruitment and selection policy by means of a preliminary exploratory study. In addition to this, the objective was the need to establish the various techniques or methods in use to recruit and select candidates for vacant posts. Motivation for the study: To develop a better understanding of the trends in the application of recruitment and selection methods within the Eastern Cape. Research design, approach and method: This study has a non-experimental design. Methodological processes followed a qualitative and quantitative mixed approach. Structured interviews were used to collect data followed by a descriptive statistical analysis, summary and interpretation of results. Main findings: Whereas newspaper advertising and recruitment agencies are the most popular recruitment methods, the application blank and interviews were mostly preferred for selection purposes. Although assessment centres and psychological assessments were also regarded as popular selection methods, assessment centres were; however, the most prominent selection method to follow of the above two mentioned selection methods. Practical/managerial implications: The research findings could provide corporate leaders and their human resource functionaries with a theoretical pointer relative to recruitment and selection trends within the Province which could guide more effective skills attraction and selection decisions. Contribution/value-add: The study provided valuable strategic information to improve on organisational competiveness via effective recruitment and selection processes. In addition, training and educational programmes could eventually fill the needs and gaps identified in

  5. Predictors of Stress Fracture Susceptibility in Young Female Recruits

    Science.gov (United States)

    2004-09-02

    in U.S. Army Combat Medic Advanced individual training. Mil Med. 2000;165:647-652. 15. Hulkko A, Orava S. Stress fractures in athletes . Int J Sports ...379. 24. Miller C, Major N, Toth A. Pelvic stress injuries in the athlete : management and prevention. Sports Med. 2003;33:1003-1012. 25. Myburgh...recruits than has been reported in civilian athletes or male military recruits. Pelvic stress fractures are relatively rare in civilian male and female

  6. Recruiting Implications of the Long War for the Marine Corps

    Science.gov (United States)

    2008-01-01

    nation’s elite are refraining from service. Recommendations are provided to sustain positive trends and reverse negative trends in attracting ample...INTRODUCTION 1 RECRUITING BASE: THE MILLENIALS 2 QUANTITY 3 QUALITY MATTERS 5 MILLENIAL RECRUITS 9 DIVERSITy 9 AFRICAN AMERICANS SERVING LESS lO mSPANIC...reveals that the nation’s elite are refraining from service. Recommendations are provided to sustain positive trends and reverse negative trends in

  7. RECRUITMENT AND SELECTION IS AN EXERCISE IN DISCRIMINATION

    Directory of Open Access Journals (Sweden)

    Dragan Čizmić

    2013-12-01

    Full Text Available Throughout the course of this work it is examined how the ways in which both, the law of the land and the morals held by a company, can improve the process of choosing an employee. It also identified the principles of recruitment and selection which should be applied and discuss their effect upon a potential recruit. It looked into the ways in which these considerations benefit both the employer and the employee.

  8. Making the right move : investigating employers' recruitment strategies

    OpenAIRE

    GËRXHANI, Klarita; KOSTER, Ferry

    2015-01-01

    The purpose of this paper is to investigate employers’ recruitment strategies to address distinct job-related agency problems before establishing an employment relationship. Insights from agency theory and the social embeddedness perspective are combined to hypothesize whether and why employers adapt their recruitment strategies to the job type (differing in level of discretion) for which they are externally hiring. The hypotheses are empirically tested using data from a survey of 288 Dutch e...

  9. PROFESSIONALIZATION OF THE JUDICIARY BY RECRUITMENT AND SELECTION

    Directory of Open Access Journals (Sweden)

    VIORICA POPESCU

    2012-05-01

    Full Text Available Considered as key elements of the human resources policy of an organization, recruitment and selection influence the status of human potential. Given that the main resource of each judicial system is the human resource, the present study aims to analyze the means of recruitment and selection of magistrates, both from the perspective of the national legislation, as well as from the perspective of the international provisions, identifying all vulnerabilities and directions for improvement.

  10. Sexual Recruitment in Zostera marina: Progress toward a Predictive Model.

    Science.gov (United States)

    Furman, Bradley T; Peterson, Bradley J

    2015-01-01

    Ecophysiological stress and physical disturbance are capable of structuring meadows through a combination of direct biomass removal and recruitment limitation; however, predicting these effects at landscape scales has rarely been successful. To model environmental influence on sexual recruitment in perennial Zostera marina, we selected a sub-tidal, light-replete study site with seasonal extremes in temperature and wave energy. During an 8-year observation period, areal coverage increased from 4.8 to 42.7%. Gains were stepwise in pattern, attributable to annual recruitment of patches followed by centrifugal growth and coalescence. Recruitment varied from 13 to 4,894 patches per year. Using a multiple linear regression approach, we examined the association between patch appearance and relative wave energy, atmospheric condition and water temperature. Two models were developed, one appropriate for the dispersal of naked seeds, and another for rafted flowers. Results indicated that both modes of sexual recruitment varied as functions of wind, temperature, rainfall and wave energy, with a regime shift in wind-wave energy corresponding to periods of rapid colonization within our site. Temporal correlations between sexual recruitment and time-lagged climatic summaries highlighted floral induction, seed bank and small patch development as periods of vulnerability. Given global losses in seagrass coverage, regions of recovery and re-colonization will become increasingly important. Lacking landscape-scale process models for seagrass recruitment, temporally explicit statistical approaches presented here could be used to forecast colonization trajectories and to provide managers with real-time estimates of future meadow performance; i.e., when to expect a good year in terms of seagrass expansion. To facilitate use as forecasting tools, we did not use statistical composites or normalized variables as our predictors. This study, therefore, represents a first step toward linking

  11. Recruitment advantage of large seeds is greater in shaded habitats

    OpenAIRE

    Bruun, Hans Henrik; ten Brink, Dirk-Jan

    2008-01-01

    Large seeds are assumed to have higher probability of successful recruitment than small seeds. This is because larger seeds give rise to larger seedlings and larger seedlings better withstand environmental hazards like deep shade and drought. Biotic and abiotic limitations to seedling growth and survival, and conversely availability of safe sites for recruitment, vary along environmental gradients and between habitat types. Thus, the value to plant species of possessing large seeds may differ...

  12. Methodological approaches to staff recruitment at labour market

    OpenAIRE

    V.V. Bozhkova

    2016-01-01

    The aim of article. The purpose of the article is to improve and formalize methodological approaches to staff recruitment at labour markets. The results of the analysis. The integral result of the study is the following. The author systematized the main problems of the staff recruitment according to the subjects of the employment process (or their place of origin): 1) on the part of the applicants: - inflated / deflated self-esteem; - incorrect understanding of their own capabi...

  13. Estimating the Depth of the Navy Recruiting Market

    Science.gov (United States)

    2016-09-01

    not qualify for the military include obesity , aptitude, and drug use (Jordan 2014). Recruiting qualified and eligible individuals presents a...Corps recruiters were the greatest inhibitors to other services’ accessions (Gibson et al. 2011). Gibson et al. also found that as American College ...permanently disabled (IRS 2015). For ZIP codes containing or near educational institutions such as universities, the student population will not be

  14. Disclosure of investigators' recruitment performance in multicenter clinical trials

    DEFF Research Database (Denmark)

    Dal-Ré, Rafael; Moher, David; Gluud, Christian

    2011-01-01

    Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends.......Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends....

  15. Arrested recovery of Diadema antillarum population: Survival or recruitment limitation?

    Science.gov (United States)

    Rodríguez-Barreras, Ruber; Pérez, María E.; Mercado-Molina, Alex E.; Sabat, Alberto M.

    2015-09-01

    Densities of the long-spined sea urchin Diadema antillarum remain significantly below pre mass-mortality levels at most Caribbean localities. The arrested recovery of this formerly abundant herbivore has been attributed to low supply of recruits and high post settlement mortality. There is, however, some debate as to which of these factors is determinant of the local dynamics of this echinoid. In this study, we use demographic modeling to analyze the contribution of recruitment and post settlement survival on the dynamics of D. antillarum in four localities of Puerto Rico Archipelago. Our results indicate relatively high adult survival, and low stasis but high growth transition in the small individuals. Recruitment rates were low and exhibited high spatial and temporal variability. The four populations exhibited asymptotic growth rates (λ) below 1.0, with λ varying from 0.918 to 0.964. The elasticity analysis showed that the survival of large-sized Diadema can potentially contribute most to the changes in λ for all sites. Numerical projections of the populations indicate that no site would exhibit an increase in density under current recruitment rates, but doubling recruitment would produce an increase in sea urchin density in three of the four sites. Recovery of D. antillarum populations would require the spatial and temporal co-occurrence of high recruitment and survival rates.

  16. Recruitment of rural healthcare professionals for live continuing education.

    Science.gov (United States)

    Holuby, Ronnie Scott; Pellegrin, Karen L; Barbato, Anna; Ciarleglio, Anita

    2015-01-01

    The availability of rural healthcare is a growing concern in the United States as fewer healthcare providers choose to work in rural areas. Accessing quality continuing education (CE) for rural healthcare practitioners (HCPs) remains a challenge and may pose a barrier to quality care. To maximize attendance at a live, in-person, free CE program focusing on geriatric medication and issues specifically targeted to HCPs in rural areas, two methods were implemented sequentially. The first method used formal advertising implemented by a professional marketing service to promote CE events. The second method enlisted local healthcare organizations and physician groups to promote the CE event to their employees. Cost per attendee was calculated for comparison. Professional marketing services recruited 31 HCPs (March 2011) and resulted in a per-participant recruitment cost of US$428.62. Local healthcare organizations and physician groups' marketing recruited 48 HCPs (July-August 2011) and resulted in a per-participant recruitment cost of US$55.19. Providing free CE coordinated through local healthcare organizations and physician groups was the most cost-effective method of recruiting rural HCPs for CE. Formal advertising added cost without increasing the number of participants per event. Although this is the first study of the cost-effectiveness of recruitment methods targeting HCPs in rural areas, results are consistent with research on cost-effectiveness of outreach to rural lay community members.

  17. Financial Recruitment Incentive Programs for Nursing Personnel in Canada.

    Science.gov (United States)

    Mathews, Maria; Ryan, Dana

    2015-03-01

    Financial incentives are increasingly offered to recruit nursing personnel to work in underserved communities. The authors describe and compare the characteristics of federal, provincial and territorial financial recruitment incentive programs for registered nurses (RNs), nurse practitioners (NPs), licensed practical nurses (LPNs), registered practical nurses or registered psychiatric nurses. The authors identified incentive programs from government, health ministry and student aid websites and by contacting program officials. Only government-funded recruitment programs providing funding beyond the normal employee wages and benefits and requiring a service commitment were included. The authors excluded programs offered by hospitals, regional or private firms, and programs that rewarded retention. All provinces and territories except QC and NB offer financial recruitment incentive programs for RNs; six provinces (BC, AB, SK, ON, QC and NL) offer programs for NPs, and NL offers a program for LPNs. Programs include student loan forgiveness, tuition forgiveness, education bursaries, signing bonuses and relocation expenses. Programs target trainees, recent graduates and new hires. Funding and service requirements vary by program, and service requirements are not always commensurate with funding levels. This snapshot of government-funded recruitment incentives provides program managers with data to compare and improve nursing workforce recruitment initiatives. Copyright © 2015 Longwoods Publishing.

  18. Recruiting healthy volunteers for research participation via internet advertising.

    Science.gov (United States)

    Bramstedt, Katrina A

    2007-06-01

    The Internet is frequently used as a tool to recruit research subjects, and the US Food and Drug Administration (FDA) provides general guidance regarding such advertising. The goal of this study was to explore the incidence and nature of ethically inappropriate recruiting advertisements on the Internet and to provide descriptive guidance to researchers for responsible Internet recruiting. In this study, 119 advertisements recruiting health volunteers and listed on the CenterWatch Clinical Trials Listing Service website were reviewed for content as well as text style and visual effects. The majority of advertisements satisfied FDA guidance. However, 21 (18%) were ethically troubling with regard to font size, font style, and/or verbiage. In many advertisements, it was unclear if "medication" meant "investigational drug," "over-the-counter medication" or US FDA approved "prescription medication." Nearly 30% of the 119 advertisements used the terms "free," "no charge" or "no cost" as lures. Ethically problematic recruiting advertisements can be coercive and misleading. Descriptive guidance provided in this paper can help clinical researchers create ethically appropriate recruiting advertisements.

  19. Recruiting US Chinese Elders Into Clinical Research for Dementia.

    Science.gov (United States)

    Li, Clara; Neugroschl, Judith; Umpierre, Mari; Martin, Jane; Huang, QiYing; Zeng, Xiaoyi; Cai, Dongming; Sano, Mary

    2016-01-01

    This study described and evaluated the rapid recruitment of elderly Chinese into clinical research at the Mount Sinai Alzheimer's Disease Research Center (MSADRC). Methods of publicizing the study included lectures to local senior centers/churches and publications in local Chinese newspapers. The amount of time and success of these methods were evaluated. A "go to them" model of evaluation was used to enable participants to complete the study visit at locations where they were comfortable. From January to December 2015, we recruited 98 participants aged 65 years or older who primarily speak Mandarin/Cantonese and reside in New York. The mean age and years of education was 73.93±6.34 and 12.79±4.58, respectively. The majority of participants were female (65.3%) and primarily Mandarin speaking (53.1%). Of all enrollees, 54.1% were recruited from community lectures, 29.6% through newspapers, 10.2% through word of mouth, and 6.1% from our clinical services. About 40.8% of participants underwent evaluations at the MSADRC, 44.9% at local senior centers/churches, and 14.3% at home. Given that the majority of our participants had low English proficiency, the use of bilingual recruiters probably allowed us to overcome the language barrier, facilitating recruitment. Our "go to them" model of evaluation is another important factor contributing to our successful recruitment.

  20. Stimulation of the Salicylic Acid Pathway Aboveground Recruits Entomopathogenic Nematodes Belowground

    Science.gov (United States)

    Filgueiras, Camila Cramer; Willett, Denis S.; Junior, Alcides Moino; Pareja, Martin; Borai, Fahiem El; Dickson, Donald W.; Stelinski, Lukasz L.; Duncan, Larry W.

    2016-01-01

    Plant defense pathways play a critical role in mediating tritrophic interactions between plants, herbivores, and natural enemies. While the impact of plant defense pathway stimulation on natural enemies has been extensively explored aboveground, belowground ramifications of plant defense pathway stimulation are equally important in regulating subterranean pests and still require more attention. Here we investigate the effect of aboveground stimulation of the salicylic acid pathway through foliar application of the elicitor methyl salicylate on belowground recruitment of the entomopathogenic nematode, Steinernema diaprepesi. Also, we implicate a specific root-derived volatile that attracts S. diaprepesi belowground following aboveground plant stimulation by an elicitor. In four-choice olfactometer assays, citrus plants treated with foliar applications of methyl salicylate recruited S. diaprepesi in the absence of weevil feeding as compared with negative controls. Additionally, analysis of root volatile profiles of citrus plants receiving foliar application of methyl salicylate revealed production of d-limonene, which was absent in negative controls. The entomopathogenic nematode S. diaprepesi was recruited to d-limonene in two-choice olfactometer trials. These results reinforce the critical role of plant defense pathways in mediating tritrophic interactions, suggest a broad role for plant defense pathway signaling belowground, and hint at sophisticated plant responses to pest complexes. PMID:27136916

  1. U.S. Navy Chaplain Corps Recruiting: Ideas to Boost Deficiencies with Recruiting and Assessing of Chaplains

    National Research Council Canada - National Science Library

    McGuffin, Frederick A

    2008-01-01

    This study explores the need for incentives for Navy Chaplain Corps recruiting and recommends changes in the existing incentive program and a potential change to the way the Navy accesses chaplains...

  2. Specific recruitment of circulating angiogenic cells using biomaterials as filters.

    Science.gov (United States)

    Parlato, Matthew; Molenda, James; Murphy, William L

    2017-07-01

    Endogenous recruitment of circulating angiogenic cells (CACs) is an emerging strategy to induce angiogenesis within a defect site, and multiple recent strategies have deployed soluble protein releasing biomaterials for this purpose. However, the way in which the design of biomaterials affects CAC recruitment and invasion are poorly understood. Here we used an enhanced-throughput cell invasion assay to systematically examine the effects of biomaterial design on CAC recruitment. The screens co-optimized hydrogel presentation of a stromal-derived factor-1α (SDF-1α) gradient, hydrogel degradability, and hydrogel stiffness for maximal CAC invasion. We also examined the specificity of this invasion by assessing dermal fibroblast, mesenchymal stem cell, and lymphocyte invasion individually and in co-culture with CACs to identify hydrogels specific to CAC invasion. These screens suggested a subset of MMP-degradable hydrogels presenting a specific range of SDF-1α gradient slopes that induced specific invasion of CACs, and we posit that the design parameters of this subset of hydrogels may serve as instructive templates for the future design of biomaterials to specifically recruit CACs. We also posit that this design concept may be applied more broadly in that it may be possible to utilize these specific subsets of biomaterials as "filters" to control which types of cell populations invade into and populate the biomaterial. The recruitment of specific cell types for cell-based therapies in vivo is of great interest to the regenerative medicine community. Circulating angiogenic cells (CACs), CD133+ cells derived from the blood stream, are of particular interest for induction of angiogenesis in ischemic tissues, and recent studies utilizing soluble-factor releasing biomaterials to recruit these cells in vivo show great promise. However, these studies are largely "proof of concept" and are not systematic in nature. Thus, little is currently known about how biomaterial design

  3. Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes

    Directory of Open Access Journals (Sweden)

    Geun Hyang Kim

    2015-03-01

    Conclusions: Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism.

  4. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

    OpenAIRE

    Dorhoi, Anca; Iannaccone, Marco; Farinacci, Maura; Faé, Kellen C.; Schreiber, Jörg; Moura-Alves, Pedro; Nouailles, Geraldine; Mollenkopf, Hans-Joachim; Oberbeck-Müller, Dagmar; Jörg, Sabine; Heinemann, Ellen; Hahnke, Karin; Löwe, Delia; Del Nonno, Franca; Goletti, Delia

    2013-01-01

    The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in...

  5. Determining the requirements for e-selection in a small recruitment company - using the regulative cycle

    NARCIS (Netherlands)

    Bondarouk, Tatiana; Ruel, Hubertus Johannes Maria; Timmermans, P.; Buragga, K.A.; Zaman, N.

    2013-01-01

    The requirements for e-selection technology to be of practical use for Company T have been investigated. Company T’s main business is in identifying and seconding personnel, especially in the technical sector, and it had been anticipating a shortage in the supply of candidates. This served as the

  6. In situ Analysis of Coral Recruits Using Fluorescence Imaging

    Directory of Open Access Journals (Sweden)

    Adi Zweifler

    2017-09-01

    Full Text Available Recruitment is a fundamental process that influences coral population dynamics as well as reef community structure. To date, coral recruitment success rates are poorly quantified because survey methods are labor-intensive and require manual interpretation. Thus, they are prone to human errors and have low repeatability—a gap we aim to bridge in this research. Since both corals and their symbiotic algae contain fluorescent pigments (chlorophyll and fluorescent proteins, we used the non-invasive Fluorescence Imaging System (FluorIS and developed a methodology to acquire daytime fluorescent photographs and identify coral recruits in them. We tested our method by monitoring 20 random quadrats at two sites in the Gulf of Aqaba, Israel. The quadrats were surveyed once a month for 8 months in order to track the settlement, mortality and survival rates of new coral recruits. We demonstrate daytime imaging using our method and identification of coral recruits as small as 1 mm in diameter, in a 20 × 20 cm quadrat. Our results show that this photographic method reduces surveyor errors and improves precision. The surveys revealed that on average, there are ~2 new coral recruit settlements (<2 cm for a quadrat (40 cm2 per month and that 83% of them survive the first month. Our study suggests a relative stability in the Gulf of Aqaba coral population during the survey period. The ability to survey recruits during the day using low-cost, easy-to-use photographic equipment has the potential to contribute significantly to the standardization of coral reef monitoring and management tools, at a time when the world's coral reefs are declining due to local and global stressors.

  7. Effective recruitment and retention strategies in community health programs.

    Science.gov (United States)

    McCann, Jennifer; Ridgers, Nicola D; Carver, Alison; Thornton, Lukar E; Teychenne, Megan

    2013-08-01

    The aim of this project was to identify effective recruitment and retention strategies used by health-promotion organisations that focus on increasing physical activity and improving nutrition within the local community. Semistructured telephone or face-to-face interviews with 25 key informants from stakeholder organisations were conducted. Key informants discussed strategies used by their organisation to effectively recruit and retain participants into community-based healthy eating and/or physical activity programs. Transcribed data were analysed with NVivo software. Effective recruitment strategies included word of mouth, links with organisations, dissemination of printed materials, media, referrals, cross-promotion of programs and face-to-face methods. Effective retention strategies included encouraging a sense of community ownership, social opportunities, recruiting a suitable leader and offering flexibility and support. Fees and support for recruiting and retaining participants was also identified. This study provides novel insights to a greatly under researched topic in the field of health promotion. There are two key take-home messages from the present study that are applicable to health practitioners as well as developers and deliverers of community health-promotion programs: (1) it is imperative that all community health organisations report on the effectiveness of their recruitment and retention, both successes and failures; and (2) there is a clear need to tailor the recruitment and retention approach to the target population and the setting the program is occurring in. SO WHAT? These findings provide important insights for the development of future community-based healthy eating and physical activity programs.

  8. Determining correlation between Emerita analoga recruitment and coastal upwelling (Invited)

    Science.gov (United States)

    Wong, K.; Godoy, E.; Dean, A.; Johnson, R.

    2009-12-01

    Since 2003, Careers in Science (CiS) interns have been participating in the Farallones Marine Sanctuary Association's Long-term Monitoring Program and Experiential Training for Students (LiMPETS) program monitoring populations of Emerita analoga, the Pacific mole crab. The CiS intern program at the California Academy of Sciences is a multi-year, year-round work-based science education and youth development program for young people from groups typically under-represented in the sciences. E. analoga, an inhabitant of sandy beach swash zone, plays an essential role in marine food webs. Recent studies have suggested E. analoga to be indicators of DDT and domoic acid in the ecosystem. My peers and I collected E. analoga to determine population demographics, including size and sex. On a weekly basis during the months of June, July and August, at San Francisco’s Ocean Beach in Golden Gate National Recreational Area we systematically collect live samples and data for the population monitoring. From June to August 2009, field observations indicated the most abundant E. analoga recruit populations since 2003. After observing this change, we wanted to find possible causes for the increase in recruits. We hypothesized that there was a correlation between recruit population and coastal upwelling events because of the increased nutrient availability due to the events. We compared recruit population data from 2003 through 2009 to upwelling anomalies off the coast of San Francisco. We did not find an increased recruit population 4 to 5 months after an upwelling event, which is the time needed for E. analoga to develop from its planktonic stage to a recruit. One implication of our comparison is that upwelling events cannot be directly correlated with successful recruiting of E. analoga.

  9. ARF1 recruits RAC1 to leading edge in neutrophil chemotaxis.

    Science.gov (United States)

    Mazaki, Yuichi; Onodera, Yasuhito; Higashi, Tsunehito; Horinouchi, Takahiro; Oikawa, Tsukasa; Sabe, Hisataka

    2017-10-02

    The small GTPase ARF1 mediates membrane trafficking mostly from the Golgi, and is essential for the G protein-coupled receptor (GPCR)-mediated chemotaxis of neutrophils. In this process, ARF1 is activated by the guanine nucleotide exchanger GBF1, and is inactivated by the GTPase-activating protein GIT2. Neutrophils generate the Gβγ-PAK1-αPIX-GIT2 linear complex during GPCR-induced chemotaxis, in which αPIX activates RAC1/CDC42, which then employs PAK1. However, it has remained unclear as to why GIT2 is included in this complex. We investigated the association between ARF1 and RAC1/CDC42 during the fMLP-stimulated chemotaxis of HL60 cells. We found that the silencing of GBF1 significantly impaired the recruitment of RAC1 to the leading edges, but not PAK1, αPIX, RAC2, or CDC42. A significant population of RAC1 colocalized with ARF1 at the leading edges in stimulated cells, whereas fMLP activated both ARF1 and ARF5. Consistently, the silencing of ARF1, but not ARF5, impaired the recruitment of RAC1, whereas the silencing of RAC1 did not affect the recruitment of ARF1 to the leading edges. Our results indicated that the activation of ARF1 triggers the plasma membrane recruitment of RAC1 in GPCR-mediated chemotaxis, which is essential for cortical actin remodeling. Thus, membrane remodeling at the leading edges appears to precede actin remodeling in chemotaxis. Together with the fact that GIT2, which inactivates ARF1, is an integral component of the machinery activating RAC1, we proposed a model in which the ARF1-RAC1 linkage enables the regulation of ARF1 by repetitive on/off cycles during GPCR-mediated neutrophil chemotaxis.

  10. Effect of adaptability of field army recruits to psychological education

    Directory of Open Access Journals (Sweden)

    Meng-xue ZHAO

    2015-07-01

    Full Text Available Objective To explore the effect of psychological education adaptability on the mental quality and mental health of recruits of field army units. Methods A total number of 1244 recruits who joined the army in 2012 were tested with Mental Quality Questionnaire of Armyman (MQQA, Symptom Checklist 90 (SCL-90, Self-rating Anxiety Scale (SAS, Selfrating Depression Scale (SDS, State-Trait Anxiety Inventory (STAI, and self-compiled questionnaire for adaptability psychological education. 568 recruits received adaptability psychological education for 10 times (sessions in the experimental group, and 676 in the control group did not receive the education. Results After intervention, each dimension score of experimental and control groups on MQQA significantly increased (P0.05. Psychological education showed a significant effect on improving mental quality (P0.05. After education, the anxiety, depression, state-trait anxiety scores of the two groups reduced significantly (P<0.001; compared with the control group, the anxious emotion was effectively relieved by psychological education in experimental group (P<0.001. The recruits in the experimental group showed significant difference in 30 subjective evaluation items between before- and after-education periods (P<0.001. Conclusions The adaptability psychological education has a significant effect on promoting the mental quality, mental health, emotional state and positive cognition of the recruits in field army units. DOI: 10.11855/j.issn.0577-7402.2015.06.15

  11. Overcoming recruitment challenges in construction safety intervention research.

    Science.gov (United States)

    Kidd, Pamela; Parshall, Mark; Wojcik, Susan; Struttmann, Tim

    2004-03-01

    Recruiting workers in small construction companies and securing their participation in voluntary safety programs or safety research poses unique challenges. Worker turnover and worksite changes contribute to difficulties in locating and enrolling participants. Economic pressures and time demands potentially threaten ongoing participation. Six simulation exercises designed to reduce back and fall injuries in small construction companies were developed based on data from focus groups of workers and company owners. Working with a workers' compensation insurer, we had access to owner-operators of general, heavy, and special trade construction companies reporting less than $10,000 in payroll expenses. Recruitment methods included a participation incentive, mailed invitations followed by phone contacts, and follow-up reminders. Despite using recruitment methods recommended in the literature, participation rates were low over a 2-year intervention period. Because of these difficulties, factors affecting participation or nonparticipation became an additional research focus. Owners' perceptions of already having a good safety record and of the time demands of participation were the most commonly cited reasons for not participating. Literature on recruitment emphasizes processes and procedures under investigator control rather than understanding potential participants' judgments about the adequacy of their existing practices and the potential benefits of intervention participation relative to potential time and productivity trade-offs. Greater attention to such judgments may enhance recruitment and participation in under-studied and difficult to access populations. Copyright 2004 Wiley-Liss, Inc.

  12. Recruitment of two Opuntia species invading abandoned olive groves

    Science.gov (United States)

    Gimeno, Isabel; Vilà, Montserrat

    2002-08-01

    In Europe, many agricultural areas are now abandoned and hence can be invaded by exotic species. The abundance and spatial distribution patterns of two Opuntia species were studied in old olive groves in the Parc Natural del Cap de Creus, Catalonia (Spain). Seedling recruitment (97.3% and 51.5% of juveniles for O. maxima and O. stricta, respectively) was higher than recruitment by cladodes. O. maxima had more seedlings recruited beneath olive trees and beneath Opuntia adults than expected. Most O. stricta seedlings were also located beneath Opuntia adult plants. However, although most seedlings were recruited beneath Opuntia, some (10-30%) were found away from putative parental plants. This may be due to seed dispersal by birds and wild boars. Seeds dispersed by wild boars were not significantly more viable than seeds from intact fruits. Seedlings grow very slowly but have a high survival rate. In conclusion, Opuntia seedling recruitment is very successful and ensures the persistence of these species within old olive groves. Consequently, it prevents restoration from an agricultural land-use back to the native community.

  13. Recruiting for Epigenetic Research: Facilitating the Informed Consent Process

    Directory of Open Access Journals (Sweden)

    Nancy Jallo

    2013-01-01

    Full Text Available Because the effects of epigenetic (gene-environment interaction changes have been associated with numerous adverse health states, the study of epigenetic measures provides exciting research opportunities for biobehavioral scientists. However, recruitment for studies focusing on any aspect of genetics poses challenges. Multiple factors, including lack of knowledge regarding a research study, have been identified as barriers to recruitment. Strengthening the informed consent process through extended discussion has been found to be effective in recruiting for research studies in general, yet there is a paucity of information that focused on such a recruitment strategy for epigenetic studies. In this paper, we share our experiences with strategies to strengthen the informed consent process as well as provide samples of materials developed to heighten potential participants’ understanding of epigenetics, in 4 epigenetic research studies with women from diverse backgrounds experiencing a range of health issues. The combined enrollment success rate for epigenetic studies using the process was 89% with participants representing a diverse population. We posit that carefully developed recruitment scripts provided a foundation for improving potential participants’ understanding of the research project. Easy to understand illustrations of the epigenetic process provided a basis for active engagement and encouraged individual questions.

  14. Participant Recruitment and Engagement in Automated eHealth Trial Registration: Challenges and Opportunities for Recruiting Women Who Experience Violence.

    Science.gov (United States)

    Koziol-McLain, Jane; McLean, Christine; Rohan, Maheswaran; Sisk, Rose; Dobbs, Terry; Nada-Raja, Shyamala; Wilson, Denise; Vandal, Alain C

    2016-10-25

    Automated eHealth Web-based research trials offer people an accessible, confidential opportunity to engage in research that matters to them. eHealth trials may be particularly useful for sensitive issues when seeking health care may be accompanied by shame and mistrust. Yet little is known about people's early engagement with eHealth trials, from recruitment to preintervention autoregistration processes. A recent randomized controlled trial that tested the effectiveness of an eHealth safety decision aid for New Zealand women in the general population who experienced intimate partner violence (isafe) provided the opportunity to examine recruitment and preintervention participant engagement with a fully automated Web-based registration process. The trial aimed to recruit 340 women within 24 months. The objective of our study was to examine participant preintervention engagement and recruitment efficiency for the isafe trial, and to analyze dropout through the registration pathway, from recruitment to eligibility screening and consent, to completion of baseline measures. In this case study, data collection sources included the trial recruitment log, Google Analytics reports, registration and program metadata, and costs. Analysis included a qualitative narrative of the recruitment experience and descriptive statistics of preintervention participant engagement and dropout rates. A Koyck model investigated the relationship between Web-based online marketing website advertisements (ads) and participant accrual. The isafe trial was launched on September 17, 2012. Placement of ads in an online classified advertising platform increased the average number of recruited participants per month from 2 to 25. Over the 23-month recruitment period, the registration website recorded 4176 unique visitors. Among 1003 women meeting eligibility criteria, 51.55% (517) consented to participate; among the 501 women who enrolled (consented, validated, and randomized), 412 (82.2%) were

  15. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling

    DEFF Research Database (Denmark)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook

    2015-01-01

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and......A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co......-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated...... gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic...

  16. Genome-wide endogenous DAF-16/FOXO recruitment dynamics during lowered insulin signalling in C. elegans.

    Science.gov (United States)

    Kumar, Neeraj; Jain, Vaibhav; Singh, Anupama; Jagtap, Urmila; Verma, Sonia; Mukhopadhyay, Arnab

    2015-12-08

    Lowering insulin-IGF-1-like signalling (IIS) activates FOXO transcription factors (TF) to extend life span across species. To study the dynamics of FOXO chromatin occupancy under this condition in C. elegans, we report the first recruitment profile of endogenous DAF-16 and show that the response is conserved. DAF-16 predominantly acts as a transcriptional activator and binding within the 0.5 kb promoter-proximal region results in maximum induction of downstream targets that code for proteins involved in detoxification and longevity. Interestingly, genes that are activated under low IIS already have higher DAF-16 recruited to their promoters in WT. DAF-16 binds to variants of the FOXO consensus sequence in the promoter proximal regions of genes that are exclusively targeted during low IIS. We also define a set of 'core' direct targets, after comparing multiple studies, which tend to co-express and contribute robustly towards IIS-associated phenotypes. Additionally, we show that nuclear hormone receptor DAF-12 as well as zinc-finger TF EOR-1 may bind DNA in close proximity to DAF-16 and distinct TF classes that are direct targets of DAF-16 may be instrumental in regulating its indirect targets. Together, our study provides fundamental insights into the transcriptional biology of FOXO/DAF-16 and gene regulation downstream of the IIS pathway.

  17. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

    OpenAIRE

    Tukachinsky, Hanna; Lopez, Lyle V.; Salic, Adrian

    2010-01-01

    In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in wh...

  18. MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria

    OpenAIRE

    Chong Teik Tan; Qi-Ling Zhou; Yu-Chin Su; Nai Yang Fu; Hao-Chun Chang; Ran N. Tao; Sunil K. Sukumaran; Shairaz Baksh; Yee-Joo Tan; Kanaga Sabapathy; Chun-Dong Yu; Victor C. Yu

    2016-01-01

    Fas apoptotic signaling regulates diverse physiological processes. Acute activation of Fas signaling triggers massive apoptosis in liver. Upon Fas receptor stimulation, the BH3-only protein Bid is cleaved into the active form, tBid. Subsequent tBid recruitment to mitochondria, which is facilitated by its receptor MTCH2 at the outer mitochondrial membrane (OMM), is a critical step for commitment to apoptosis via the effector proteins Bax or Bak. MOAP-1 is a Bax-binding protein enriched at the ...

  19. Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies.

    Science.gov (United States)

    Schipper-Krom, Sabine; Juenemann, Katrin; Jansen, Anne H; Wiemhoefer, Anne; van den Nieuwendijk, Rianne; Smith, Donna L; Hink, Mark A; Bates, Gillian P; Overkleeft, Hermen; Ovaa, Huib; Reits, Eric

    2014-01-03

    Neurodegenerative disorders such as Huntington's disease are hallmarked by neuronal intracellular inclusion body formation. Whether proteasomes are irreversibly recruited into inclusion bodies in these protein misfolding disorders is a controversial subject. In addition, it has been proposed that the proteasomes may become clogged by the aggregated protein fragments, leading to impairment of the ubiquitin-proteasome system. Here, we show by fluorescence pulse-chase experiments in living cells that proteasomes are dynamically and reversibly recruited into inclusion bodies. As these recruited proteasomes remain catalytically active and accessible to substrates, our results challenge the concept of proteasome sequestration and impairment in Huntington's disease, and support the reported absence of proteasome impairment in mouse models of Huntington's disease. Copyright © 2013 Federation of European Biochemical Societies. All rights reserved.

  20. DISTANCE AS KEY FACTOR IN MODELLING STUDENTS’ RECRUITMENT BY UNIVERSITIES

    Directory of Open Access Journals (Sweden)

    SIMONA MĂLĂESCU

    2015-10-01

    Full Text Available Distance as Key Factor in Modelling Students’ Recruitment by Universities. In a previous paper analysing the challenge of keeping up with the current methodologies in the analysis and modelling of students’ recruitment by universities in the case of some ECE countries which still don’t register or develop key data to take advantage from the state of the art knowledge on the domain, we have promised to approach the factor distance in a future work due to the extent of the topic. This paper fulfill that promise bringing a review of the literature especially dealing with modelling the geographical area of recruiting students of an university, where combining distance with the proximate key factors previously reviewed, complete the meta-analysis of existing literature we have started a year ago. Beyond the theoretical benefit from a practical perspective, the metaanalysis aimed at synthesizing elements of good practice that can be applied to the local university system.