Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

Science.gov (United States)

Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

2015-01-02

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

Science.gov (United States)

Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

2011-01-01

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

An Elk transcription factor is required for Runx-dependent survival signaling in the sea urchin embryo.

Science.gov (United States)

Rizzo, Francesca; Coffman, James A; Arnone, Maria Ina

2016-08-01

Elk proteins are Ets family transcription factors that regulate cell proliferation, survival, and differentiation in response to ERK (extracellular-signal regulated kinase)-mediated phosphorylation. Here we report the embryonic expression and function of Sp-Elk, the single Elk gene of the sea urchin Strongylocentrotus purpuratus. Sp-Elk is zygotically expressed throughout the embryo beginning at late cleavage stage, with peak expression occurring at blastula stage. Morpholino antisense-mediated knockdown of Sp-Elk causes blastula-stage developmental arrest and embryo disintegration due to apoptosis, a phenotype that is rescued by wild-type Elk mRNA. Development is also rescued by Elk mRNA encoding a serine to aspartic acid substitution (S402D) that mimics ERK-mediated phosphorylation of a conserved site that enhances DNA binding, but not by Elk mRNA encoding an alanine substitution at the same site (S402A). This demonstrates both that the apoptotic phenotype of the morphants is specifically caused by Elk depletion, and that phosphorylation of serine 402 of Sp-Elk is critical for its anti-apoptotic function. Knockdown of Sp-Elk results in under-expression of several regulatory genes involved in cell fate specification, cell cycle control, and survival signaling, including the transcriptional regulator Sp-Runt-1 and its target Sp-PKC1, both of which were shown previously to be required for cell survival during embryogenesis. Both Sp-Runt-1 and Sp-PKC1 have sequences upstream of their transcription start sites that specifically bind Sp-Elk. These results indicate that Sp-Elk is the signal-dependent activator of a feed-forward gene regulatory circuit, consisting also of Sp-Runt-1 and Sp-PKC1, which actively suppresses apoptosis in the early embryo. Copyright © 2016 Elsevier Inc. All rights reserved.

The genetic algorithm for a signal enhancement

International Nuclear Information System (INIS)

Karimova, L.; Kuadykov, E.; Makarenko, N.

2004-01-01

The paper is devoted to the problem of time series enhancement, which is based on the analysis of local regularity. The model construction using this analysis does not require any a priori assumption on the structure of the noise and the functional relationship between original signal and noise. The signal itself may be nowhere differentiable with rapidly varying local regularity, what is overcome with the help of the new technique of increasing the local Hoelder regularity of the signal under research. A new signal with prescribed regularity is constructed using the genetic algorithm. This approach is applied to enhancement of time series in the paleoclimatology, solar physics, dendrochronology, meteorology and hydrology

The genetic algorithm for a signal enhancement

Energy Technology Data Exchange (ETDEWEB)

Karimova, L. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan)]. E-mail: karimova@math.kz; Kuadykov, E. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan); Makarenko, N. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan)

2004-11-21

The paper is devoted to the problem of time series enhancement, which is based on the analysis of local regularity. The model construction using this analysis does not require any a priori assumption on the structure of the noise and the functional relationship between original signal and noise. The signal itself may be nowhere differentiable with rapidly varying local regularity, what is overcome with the help of the new technique of increasing the local Hoelder regularity of the signal under research. A new signal with prescribed regularity is constructed using the genetic algorithm. This approach is applied to enhancement of time series in the paleoclimatology, solar physics, dendrochronology, meteorology and hydrology.

Hepatocellular carcinoma: clinical significance of signal heterogeneity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging

Energy Technology Data Exchange (ETDEWEB)

Fujita, Nobuhiro; Nishie, Akihiro; Asayama, Yoshiki; Ushijima, Yasuhiro; Moirta, Koichiro; Honda, Hiroshi [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Kubo, Yuichiro; Aishima, Shinichi [Kyushu University, Department of Anatomic Pathology, Graduate School of Medical Sciences, Fukuoka (Japan); Takayama, Yukihisa [Kyushu University, Department of Molecular Imaging and Diagnosis, Graduate School of Medical Sciences, Fukuoka (Japan); Shirabe, Ken [Kyushu University, Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka (Japan)

2015-01-15

To clarify the relationship between the biological behaviour of hepatocellular carcinomas (HCCs) and their signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging with a special focus on the signal heterogeneity. A total of 68 patients with 70 pathologically proven HCCs were enrolled. On the basis of the signal intensity in the hepatobiliary phase, the lesions were classified into three groups: group 1, homogeneous hypointensity (n = 44); group 2, heterogeneous hyperintensity (n = 20); and group 3, homogeneous hyperintensity (n = 6). The clinicopathological findings were compared among the three groups. The tumour size and the serum level of protein induced by vitamin K absence or antagonist-II (PIVKA-II) were significantly higher in group 2 compared to group 1 (p = 0.0155, p = 0.0215, respectively) and compared to group 3 (p = 0.0330, p = 0.0220, respectively). The organic anion transporting polypeptide 8 (OATP8) expression in group 2 and group 3 was significantly higher than in group 1 (p < 0.0001, p < 0.0001, respectively). Group 2 showed a significantly lower disease-free survival rate compared to group 1 (p = 0.0125), and group 2 was an independent prognostic factor for disease-free survival (p = 0.0308). HCCs in the hepatobiliary phase that are heterogeneously hyperintense on gadoxetic acid-enhanced MR imaging have more malignant potential than other types of HCCs. (orig.)

Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways.

Science.gov (United States)

Nafar, F; Clarke, J P; Mearow, K M

2017-05-01

Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted

Depression of p53-independent Akt survival signals in human oral cancer cells bearing mutated p53 gene after exposure to high-LET radiation

Energy Technology Data Exchange (ETDEWEB)

Nakagawa, Yosuke [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Takahashi, Akihisa [Advanced Scientific Research Leader Development Unit, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511 (Japan); Kajihara, Atsuhisa; Yamakawa, Nobuhiro; Imai, Yuichiro [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ota, Ichiro; Okamoto, Noritomo [Department of Otorhinolaryngology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Mori, Eiichiro [Department of Radiation Oncology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Noda, Taichi [Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Furusawa, Yoshiya [Heavy-ion Radiobiology Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Kirita, Tadaaki [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ohnishi, Takeo, E-mail: tohnishi@naramed-u.ac.jp [Department of Radiation Oncology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan)

2012-07-13

Highlights: Black-Right-Pointing-Pointer High-LET radiation induces efficiently apoptosis regardless of p53 gene status. Black-Right-Pointing-Pointer We examined whether high-LET radiation depresses the Akt-survival signals. Black-Right-Pointing-Pointer High-LET radiation depresses of survival signals even in the mp53 cancer cells. Black-Right-Pointing-Pointer High-LET radiation activates Caspase-9 through depression of survival signals. Black-Right-Pointing-Pointer High-LET radiation suppresses cell growth through depression of survival signals. -- Abstract: Although mutations and deletions in the p53 tumor suppressor gene lead to resistance to low linear energy transfer (LET) radiation, high-LET radiation efficiently induces cell lethality and apoptosis regardless of the p53 gene status in cancer cells. Recently, it has been suggested that the induction of p53-independent apoptosis takes place through the activation of Caspase-9 which results in the cleavage of Caspase-3 and poly (ADP-ribose) polymerase (PARP). This study was designed to examine if high-LET radiation depresses serine/threonine protein kinase B (PKB, also known as Akt) and Akt-related proteins. Human gingival cancer cells (Ca9-22 cells) harboring a mutated p53 (mp53) gene were irradiated with 2 Gy of X-rays or Fe-ion beams. The cellular contents of Akt-related proteins participating in cell survival signaling were analyzed with Western Blotting 1, 2, 3 and 6 h after irradiation. Cell cycle distributions after irradiation were assayed with flow cytometric analysis. Akt-related protein levels decreased when cells were irradiated with high-LET radiation. High-LET radiation increased G{sub 2}/M phase arrests and suppressed the progression of the cell cycle much more efficiently when compared to low-LET radiation. These results suggest that high-LET radiation enhances apoptosis through the activation of Caspase-3 and Caspase-9, and suppresses cell growth by suppressing Akt-related signaling, even in mp

Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells

Directory of Open Access Journals (Sweden)

Joseph L. Regan

2017-12-01

Full Text Available Summary: Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs. To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT, we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival. : Colon cancer is a heterogeneous tumor driven by a subpopulation(s of therapy-resistant cancer stem cells (CSCs. Regan et al. use 3D culture models to demonstrate that CSC survival is regulated by non-canonical, SHH-dependent, PTCH1-dependent Hedgehog signaling, which acts as a positive regulator of WNT signaling to block CSC differentiation. Keywords: WNT pathway, non-canonical Hedgehog signaling, cancer stem cell, colon cancer, cancer organoid, PTCH1, HHAT, SHH

Autocrine prostaglandin E2 signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway

Science.gov (United States)

Lee, Jaetae; Lee, Young Sup

2015-01-01

The COX-2/PGE2 pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE2, in cancer survival remain unknown. Herein, we investigated PGE2-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE2 not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE2-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE2 signaling acts in an autocrine manner, and specific inhibition of PGE2 will provide a novel approach for the treatment of leukemia. [BMB Reports 2015; 48(2): 109-114] PMID:24965577

Acquirement and enhancement of remote speech signals

Science.gov (United States)

Lü, Tao; Guo, Jin; Zhang, He-yong; Yan, Chun-hui; Wang, Can-jin

2017-07-01

To address the challenges of non-cooperative and remote acoustic detection, an all-fiber laser Doppler vibrometer (LDV) is established. The all-fiber LDV system can offer the advantages of smaller size, lightweight design and robust structure, hence it is a better fit for remote speech detection. In order to improve the performance and the efficiency of LDV for long-range hearing, the speech enhancement technology based on optimally modified log-spectral amplitude (OM-LSA) algorithm is used. The experimental results show that the comprehensible speech signals within the range of 150 m can be obtained by the proposed LDV. The signal-to-noise ratio ( SNR) and mean opinion score ( MOS) of the LDV speech signal can be increased by 100% and 27%, respectively, by using the speech enhancement technology. This all-fiber LDV, which combines the speech enhancement technology, can meet the practical demand in engineering.

Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

Science.gov (United States)

Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

2015-12-01

Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

Science.gov (United States)

Hu, Peizhen; Chung, Leland W K; Berel, Dror; Frierson, Henry F; Yang, Hua; Liu, Chunyan; Wang, Ruoxiang; Li, Qinlong; Rogatko, Andre; Zhau, Haiyen E

2013-01-01

We reported (PLoS One 6 (12):e28670, 2011) that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC) tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE) tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1) expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

Ras and Rheb Signaling in Survival and Cell Death

International Nuclear Information System (INIS)

Ehrkamp, Anja; Herrmann, Christian; Stoll, Raphael; Heumann, Rolf

2013-01-01

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

Ras and Rheb Signaling in Survival and Cell Death

Energy Technology Data Exchange (ETDEWEB)

Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: rolf.heumann@rub.de [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)

2013-05-28

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

LENUS (Irish Health Repository)

Gupta, Sanjeev

2010-01-01

Endoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha\\/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.

RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3β activity

International Nuclear Information System (INIS)

Lee, Cheol-Jung; Lee, Mee-Hyun; Lee, Ji-Young; Song, Ji Hong; Lee, Hye Suk; Cho, Yong-Yeon

2013-01-01

Highlights: •We demonstrated a novel function of RSK2 in stress tolerance. •RSK2 deficiency enhanced apoptosis by calcium stress. •RSK2-mediated GSK3β phosphorylation at serine 9 increased calcium-induced stress tolerance. •Calcium stress-induced apoptosis inhibited by adding back of RSK2 into RSK2 −/− MEFs. -- Abstract: Our previous studies demonstrated that RSK2 plays a key role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor (EGF) in mouse and human skin cells. However, no direct evidence has been found regarding the relationship of RSK2 and cell survival. In this study, we found that RSK2 interacted and phosphorylated GSK3β at Ser9. Notably, GSK3β phosphorylation at Ser9 was suppressed in RSK2 −/− MEFs compared with RSK2 +/+ MEFs by stimulation of EGF and calcium ionophore A23187, a cellular calcium stressor. In proliferation, we found that RSK2 deficiency suppressed cell proliferation compared with RSK2 +/+ MEFs. In contrast, GSK3β −/− MEFs induced the cell proliferation compared with GSK3β +/+ MEFs. Importantly, RSK2 −/− MEFs were induced severe cellular morphology change by A23187 and enhanced G1/G0 and sub-G1 accumulation of the cell cycle phase compared with RSK2 +/+ MEFs. The sub-G1 induction in RSK2 −/− MEFs by A23187 was correlated with increase of cytochrome c release, caspase-3 cleavage and apoptotic DNA fragmentation compared with RSK2 +/+ MEFs. Notably, return back of RSK2 into RSK2 −/− MEFs restored A23187-induced morphological change, and decreased apoptosis, apoptotic DNA fragmentation and caspase-3 induction compared with RSK2 −/− /mock MEFs. Taken together, our results demonstrated that RSK2 plays an important role in stress-tolerance and cell survival, resulting in cell proliferation and cancer development

Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

Directory of Open Access Journals (Sweden)

Peizhen Hu

Full Text Available We reported (PLoS One 6 (12:e28670, 2011 that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1 expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

Signal-enhancement reflective pulse oximeter with Fresnel lens

Science.gov (United States)

Chung, Shuang-Chao; Sun, Ching-Cherng

2016-09-01

In this paper, a new reflective pulse oximeter is proposed and demonstrated with implanting a Fresnel lens, which enhances the reflected signal. An optical simulation model incorporated with human skin characteristics is presented to evaluate the capability of the Fresnel lens. In addition, the distance between the light emitting diode and the photodiode is optimized. Compared with the other reflective oximeters, the reflected signal light detected by the photodiode is enhanced to more than 140%.

Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts

Directory of Open Access Journals (Sweden)

Wen-Hsiung Chan

2008-05-01

Full Text Available Caffeine consumption is a risk factor for osteoporosis, but the precise regulatory mechanisms are currently unknown. Here, we show that cell viability decreases in osteoblasts treated with caffeine in a dose-dependent manner. This cell death is attributed primarily to apoptosis and to a smaller extent, necrosis. Moreover, caffeine directly stimulates intracellular oxidative stress. Our data support caffeine-induced apoptosis in osteoblasts via a mitochondria-dependent pathway. The apoptotic biochemical changes were effectively prevented upon pretreatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the caffeine-induced apoptotic cascade. Additionally, p21-activated protein kinase 2 (PAK2 and c-Jun N-terminal kinase (JNK were activated in caffeine-treated osteoblasts. Experiments further found that PAK2 activity is required for caffeine-induced JNK activation and apoptosis. Importantly, our data also show that caffeine triggers cell death via inactivation of the survival signal, including the ERK- and Akt-mediated anti-apoptotic pathways. Finally, exposure of rats to dietary water containing 10~20 μM caffeine led to bone mineral density loss. These results demonstrate for the first time that caffeine triggers apoptosis in osteoblasts via activation of mitochondria-dependent cell death signaling and inactivation of the survival signal, and causes bone mineral density loss in vivo.

Signal enhancement with variable span linear filters

CERN Document Server

Benesty, Jacob; Jensen, Jesper R

2016-01-01

This book introduces readers to the novel concept of variable span speech enhancement filters, and demonstrates how it can be used for effective noise reduction in various ways. Further, the book provides the accompanying Matlab code, allowing readers to easily implement the main ideas discussed. Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal-to-noise ratio, Wiener, and tradeoff filters (including their new generalizations) can be obtained using the variable span filter framework. It then illustrates how the variable span filters can be applied in various contexts, namely in single-channel STFT-based enhancement, in multichannel enhancement in both the time and STFT domains, and, lastly, in time-domain binaural enhancement. In these contexts, the properties of ...

Prolonged sulforaphane treatment activates survival signaling in nontumorigenic NCM460 colon cells but apoptotic signaling in tumorigenic HCT116 colon cells.

Science.gov (United States)

Zeng, Huawei; Trujillo, Olivia N; Moyer, Mary P; Botnen, James H

2011-01-01

Sulforaphane (SFN) is a naturally occurring chemopreventive agent; the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon cancer and normal cells. In this study, we demonstrated that SFN (15 μmol/L) exposure (72 h) inhibited cell proliferation by up to 95% in colon cancer cells (HCT116) and by 52% in normal colon mucosa-derived (NCM460) cells. Our data also showed that SFN exposure (5 and 10 μmol/L) led to the reduction of G1 phase cell distribution and an induction of apoptosis in HCT116 cells, but to a much lesser extent in NCM460 cells. Furthermore, the examination of mitogen-activated protein kinase (MAPK) signaling status revealed that SFN upregulated the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) in NCM460 cells but not in HCT116 cells. In contrast, SFN enhanced the phosphorylation of stress-activated protein kinase (SAPK) and decreased cellular myelocytomatosis oncogene (c-Myc) expression in HCT116 cells but not NCM460 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic signaling in HCT116 cells may play a critical role in SFN's stronger potential of inhibiting cell proliferation in colon cancer cells than in normal colon cells. Copyright © 2011, Taylor & Francis Group, LLC

S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis.

Science.gov (United States)

Hou, JinChao; Chen, QiXing; Wu, XiaoLiang; Zhao, DongYan; Reuveni, Hadas; Licht, Tamar; Xu, MengLong; Hu, Hu; Hoeft, Andreas; Ben-Sasson, Shmuel A; Shu, Qiang; Fang, XiangMing

2017-12-15

Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. To investigate the role of S1PR3 in antibacterial immunity during sepsis. Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3 -/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3 -/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3 -/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

Ultrasonic correlator versus signal averager as a signal to noise enhancement instrument

Science.gov (United States)

Kishoni, Doron; Pietsch, Benjamin E.

1989-01-01

Ultrasonic inspection of thick and attenuating materials is hampered by the reduced amplitudes of the propagated waves to a degree that the noise is too high to enable meaningful interpretation of the data. In order to overcome the low Signal to Noise (S/N) ratio, a correlation technique has been developed. In this method, a continuous pseudo-random pattern generated digitally is transmitted and detected by piezoelectric transducers. A correlation is performed in the instrument between the received signal and a variable delayed image of the transmitted one. The result is shown to be proportional to the impulse response of the investigated material, analogous to a signal received from a pulsed system, with an improved S/N ratio. The degree of S/N enhancement depends on the sweep rate. This paper describes the correlator, and compares it to the method of enhancing S/N ratio by averaging the signals. The similarities and differences between the two are highlighted and the potential advantage of the correlator system is explained.

Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.

Directory of Open Access Journals (Sweden)

Channakeshava Sokke Umeshappa

Full Text Available Involvement of CD4(+ helper T (Th cells is crucial for CD8(+ cytotoxic T lymphocyte (CTL-mediated immunity. However, CD4(+ Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA-pulsed dendritic cell (DCova. CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I complex signaling, CD4(+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2 and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7 molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.

Science.gov (United States)

Umeshappa, Channakeshava Sokke; Xie, Yufeng; Xu, Shulin; Nanjundappa, Roopa Hebbandi; Freywald, Andrew; Deng, Yulin; Ma, Hong; Xiang, Jim

2013-01-01

Involvement of CD4(+) helper T (Th) cells is crucial for CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4(+) Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+) Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+) T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b)/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4(+) Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+) Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+) Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines.

Science.gov (United States)

Clay, Timothy M; Osada, Takuya; Hartman, Zachary C; Hobeika, Amy; Devi, Gayathri; Morse, Michael A; Lyerly, H Kim

2011-04-01

Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.

Signal Enhancement with Variable Span Linear Filters

DEFF Research Database (Denmark)

Benesty, Jacob; Christensen, Mads Græsbøll; Jensen, Jesper Rindom

This book introduces readers to the novel concept of variable span speech enhancement filters, and demonstrates how it can be used for effective noise reduction in various ways. Further, the book provides the accompanying Matlab code, allowing readers to easily implement the main ideas discussed....... Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal......-to-noise ratio, Wiener, and tradeoff filters (including their new generalizations) can be obtained using the variable span filter framework. It then illustrates how the variable span filters can be applied in various contexts, namely in single-channel STFT-based enhancement, in multichannel enhancement in both...

Experimental assessment of fluorescence microscopy signal enhancement by stimulated emission

Science.gov (United States)

Dake, Fumihiro; Yazawa, Hiroki

2017-10-01

The quantity of photons generated during fluorescence microscopy is principally determined by the quantum yield of the fluorescence dyes and the optical power of the excitation beam. However, even though low quantum yields can produce poor images, it is challenging to tune this parameter, while increasing the power of the excitation beam often results in photodamage. Here, we propose the use of stimulated emission (SE) as a means of enhancing both the signal intensity and signal-to-noise ratio during confocal fluorescence microscopy. This work experimentally confirmed that both these factors can be enhanced by SE radiation, through generating a greater number of photons than are associated with the standard fluorescence signal. We also propose the concept of stimulated emission enhancing fluorescence (SEEF) microscopy, which employs both the SE and fluorescence signals, and demonstrate that the intensity of an SEEF signal is greater than those of the individual SE and fluorescence signals.

Signal enhancement by spectral equalization of high frequency broadband signals transmitted through optical fibers

International Nuclear Information System (INIS)

Lyons, P.B.; Ogle, J.W.; Holzman, M.A.

1980-01-01

A new technique is discussed for enhancing the bandwidth and intensity of high frequency (> 1 GHz) analog, spectrally broad (40 nm) signals transmitted through one kilometer of optical fiber. The existing method for bandwidth enhancement of such a signal uses a very narrow (approx. 1 nm) filter between the fiber and detector to limit bandwidth degradation due to material dispersion. Using this method, most of the available optical intensity is rejected and lost. This new technique replaces the narrow-band filter with a spectral equalizer device which uses a reflection grating to disperse the input signal spectrum and direct it onto a linear array of fibers

HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

Directory of Open Access Journals (Sweden)

Sanjeev Gupta

2010-07-01

Full Text Available Endoplasmic reticulum (ER stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR. Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.

Enhancement of Single-Channel Periodic Signals in the Time-Domain

DEFF Research Database (Denmark)

Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

2012-01-01

speech. That is, signal-dependent methods based on the signal statistics will introduce undesired distortion for some parts of speech compared to signal-independent methods based on the noise statistics. Since both the signal-independent and signal-dependent approaches to speech enhancement have...

Acute Sleep Deprivation Enhances Post-Infection Sleep and Promotes Survival during Bacterial Infection in Drosophila

Science.gov (United States)

Kuo, Tzu-Hsing; Williams, Julie A.

2014-01-01

Study Objectives: Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. Setting: Laboratory. Participants: Drosophila melanogaster. Methods and Results: Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFκB transcriptional activity as measured by a luciferase reporter (κB-luc) in living flies. Early DEP also increased NFκB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFκB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. Conclusions: Acute sleep deprivation elevated NFκB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection. Citation: Kuo TH, Williams JA. Acute sleep deprivation enhances post-infection sleep and promotes survival during bacterial infection in Drosophila. SLEEP 2014;37(5):859-869. PMID:24790264

Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.

Science.gov (United States)

Maiti, Aparna; Takabe, Kazuaki; Hait, Nitai C

2017-04-01

About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Survival of probiotic lactobacilli in acidic environments is enhanced in the presence of metabolizable sugars.

Science.gov (United States)

Corcoran, B M; Stanton, C; Fitzgerald, G F; Ross, R P

2005-06-01

Lactobacillus rhamnosus GG is an industrially significant probiotic strain with proven health benefits. In this study, the effect of glucose on L. rhamnosus GG survival was analyzed in simulated gastric juice at pH 2.0. It was found that the presence of 19.4 mM glucose resulted in up to 6-log10-enhanced survival following 90 min of exposure. Further work with dilute HCl confirmed that glucose was the sole component responsible. Comparative analysis with other Lactobacillus strains revealed that enhanced survival was apparent in all strains, but at different pH values. The presence of glucose at concentrations from 1 to 19.4 mM enhanced L. rhamnosus GG survival from 6.4 to 8 log10 CFU ml(-1) in simulated gastric juice. The mechanisms behind the protective effect of glucose were investigated. Addition of N',N'-dicyclohexylcarbodiimide to simulated gastric juice caused survival to collapse, which was indicative of a prominent role in inhibition of F0F1-ATPase. Further work with neomycin-resistant mutants that exhibited 38% to 48% of the F0F1-ATPase activity of the parent confirmed this, as the survival in the presence of glucose of these mutants decreased 3 x 10(6)-fold compared with the survival of the wild type (which had a viability of 8.02 log10 CFU ml(-1)). L. rhamnosus GG survival in acidic conditions occurred only in the presence of sugars that it could metabolize efficiently. To confirm the involvement of glycolysis in the glucose effect, iodoacetic acid was used to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. The reduction in GAPDH activity caused survival to decrease by 8.30 log10 CFU ml(-1) in the presence of glucose. The data indicate that glucose provides ATP to F0F1-ATPase via glycolysis, enabling proton exclusion and thereby enhancing survival during gastric transit.

Signal Enhancement with Variable Span Linear Filters

DEFF Research Database (Denmark)

Benesty, Jacob; Christensen, Mads Græsbøll; Jensen, Jesper Rindom

. Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal...... the time and STFT domains, and, lastly, in time-domain binaural enhancement. In these contexts, the properties of these filters are analyzed in terms of their noise reduction capabilities and desired signal distortion, and the analyses are validated and further explored in simulations....

Multichannel Signal Enhancement using Non-Causal, Time-Domain Filters

DEFF Research Database (Denmark)

Jensen, Jesper Rindom; Christensen, Mads Græsbøll; Benesty, Jacob

2013-01-01

In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non-causal. W......In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non......-causal, multichannel filters for enhancement based on an orthogonal decomposition is proposed. The evaluation shows that there is a potential gain in noise reduction and signal distortion by introducing non-causality. Moreover, experiments on real-life speech show that we can improve the perceptual quality....

Multichannel signal enhancement using a remote wireless microphone

NARCIS (Netherlands)

Bloemendal, Brian; Van De Laar, Jakob; Sommen, Piet

2012-01-01

A novel approach to multichannel signal enhancement is presented that exploits data from a remote wireless microphone (RWM). This RWM is placed near an interfering source and transmits only autocorrelation data of its observations to a host, i.e., not the entire signal. The host has access to the

RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.

Science.gov (United States)

Schouwey, K; Aydin, I T; Radtke, F; Beermann, F

2011-01-20

The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.

Ionizing radiation-induced MEK and Erk activation does not enhance survival of irradiated human squamous carcinoma cells

International Nuclear Information System (INIS)

Bonner, James A.; Vroman, Benjamin T.; Christianson, Teresa J.H.; Karnitz, Larry M.

1998-01-01

Purpose: Ionizing radiation (IR) triggers several intracellular signaling cascades that have commonly been regarded as mitogenic, including the Raf-MEK-Erk kinase cascade. In addition to promoting proliferation, activated MEK and Erk may also prevent cell death induced by cytotoxic stimuli. Because Raf, MEK, and Erk are activated by IR in some tumor cell lines, this suggests that IR-induced activation of the kinase cascade may enhance the survival of irradiated cells. Methods and Materials: IR-induced activation of MEK and Erk was assessed in irradiated UM-SCC-6 cells, a human squamous carcinoma cell line. Activation of MEK and Erk was blocked with the pharmacological inhibitor of MEK activation, PD098059. Clonogenic survival was assessed in irradiated UM-SCC-6 cells that were pretreated with nothing or with the MEK inhibitor. Results: In UM-SCC-6 cells, IR doses as low as 2 Gy rapidly activated MEK and Erk. Pretreatment of the cells with the pharmacological inhibitor of MEK activation, PD098059, effectively blocked IR-induced activation of MEK and Erk. However, inhibition of the kinase cascade did not affect the clonogenic survival of irradiated cells in either early or delayed-plating experiments. Conclusion: Taken together, these results suggest that although MEK and Erk are rapidly activated by IR treatment, these protein kinases do not affect the clonogenic survival of irradiated UM-SCC6 cells

Effect of the luminol signal enhancer on the chemiluminescence intensity and kinetics

International Nuclear Information System (INIS)

Liang Yanli; Yu Fei; Yu Songcheng; Wu Yongjun; Zhang Hongquan; Qu Lingbo

2012-01-01

The novel p-phenol derivatives, 4-(1-imidazolyl)-phenol, 4-hydroxybiphenyl, 4-hydroxy-4′-iodobiphenyl were employed as highly potent signal enhancers of luminol-hydrogen peroxide (H 2 O 2 )-horseradish peroxidase (HRP) chemiluminescence (CL) system. The CL reaction conditions were optimized, and the enhancement characteristics of these enhancers were compared with each other. The employment of these molecules greatly affected important assay parameters. Practically, the use of a novel enhancer, even a slightly change of the structure (or concentration) of 4-substituted phenol derivative, could affect assay properties quite dramatically. Furthermore, the use of different enhancers in the luminol–H 2 O 2 –HRP system can affect not only the intensity of the CL signal, which is well known, but also its kinetics. The experiment data indicated that the stronger intensity was combined with a more rapid decrease of the CL signal. - Highlights: ► 4-IMP, 4-BIP and HIOP take on different signal enhancement and light kinetics. ► The employment of 4-BIP resulted in a significant improvement of the detection limit. ► The magnitude of the signal enhancement was about 2.5-fold in the same system.

Embryo Localization Enhances the Survival of Acidovorax citrulli in Watermelon Seeds.

Science.gov (United States)

Dutta, Bhabesh; Schneider, Raymond W; Robertson, Clark L; Walcott, Ronald R

2016-04-01

-inoculated (embryo/endosperm-localized) watermelon seeds than in vacuum-infiltrated (testa-localized) seeds. Based on these results we conclude that A. citrulli cells are not intrinsically tolerant to desiccation and that localization of the bacterium to testa tissues does not enhance A. citrulli survival. In contrast, it is likely that embryo/endosperm localization enhances the survival of A. citrulli and other bacteria in seeds.

Correlation of hedgehog signal activation with chemoradiotherapy sensitivity and survival in esophageal squamous cell carcinomas

International Nuclear Information System (INIS)

Zhu Weiguo; You Zhenbin; Li Tao; Yu Changhua; Tao Guangzhou; Hu Mingli; Chen Xiaofei

2011-01-01

The objective of this study was to investigate the significance of hedgehog signaling pathway in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma. In the present study, we used the method of immunohistochemistry to examine the expression status of two hedgehog components, PTCH1 and glioma-associated oncogene GLI-1, in 100 pre-treated biopsy specimens of esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. We find that high levels of PTCH1 and GLI-1 were detected in 76.0 and 72.0% of esophageal squamous cell carcinoma, respectively. Significant associations of high PTCH1 and GLI-1 expression with large tumor size (both P=0.01), locoregional progression (P=0.001 and 0.003, respectively) and the lack of complete response to chemoradiotherapy (P=0.008 and 0.01, respectively) were observed. Univariate analysis revealed that high PTCH1 and GLI-1 expression was associated with poor locoregional progression-free survival, distant progression-free survival and overall survival. Furthermore, esophageal squamous cell carcinoma patients with high PTCH1 and GLI-1 expression have the shorter survival time than the subgroups with negative and low PTCH1 and GLI-1 expression. In multivariate analysis, PTCH1 and GLI-1 expression status were both evaluated as independent prognostic factors for locoregional progression-free survival, distant progression-free survival and overall survival. These findings suggest an important role for the activation of hedgehog signaling in esophageal squamous cell carcinoma progression and that PTCH1 and GLI-1 expression may be significantly associated with esophageal squamous cell carcinoma resistance to chemoradiotherapy. (author)

Acute sleep deprivation enhances post-infection sleep and promotes survival during bacterial infection in Drosophila.

Science.gov (United States)

Kuo, Tzu-Hsing; Williams, Julie A

2014-05-01

Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. Laboratory. Drosophila melanogaster. Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFκB transcriptional activity as measured by a luciferase reporter (κB-luc) in living flies. Early DEP also increased NFκB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFκB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. Acute sleep deprivation elevated NFκB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection.

Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress.

Directory of Open Access Journals (Sweden)

Scott M Thompson

Full Text Available Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC, but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC. Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K/mammalian target of rapamycin (mTOR dependent-protein kinase B (AKT survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3 and prognosis (AKT1. Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin.

Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

Directory of Open Access Journals (Sweden)

Hsieh Fu-Chuan

2008-10-01

Full Text Available Abstract Background Constitutive activation of signal transducer and activator of transcription 3 (Stat3 signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer. Results We found that elevated Stat3 phosphorylation in 19 of 100 (19% bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC. The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin and a cell cycle regulating gene (cyclin D1 was associated with the cell growth inhibition and apoptosis. Conclusion These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

Supramolecular Nanofibers Enhance Growth Factor Signaling by Increasing Lipid Raft Mobility

Energy Technology Data Exchange (ETDEWEB)

Newcomb, Christina J.; Sur, Shantanu; Lee, Sungsoo S.; Yu, Jeong Min; Zhou, Yan; Snead, Malcolm L.; Stupp, Samuel I. (NWU); (USC)

2016-04-12

The nanostructures of self-assembling biomaterials have been previously designed to tune the release of growth factors in order to optimize biological repair and regeneration. We report here on the discovery that weakly cohesive peptide nanostructures in terms of intermolecular hydrogen bonding, when combined with low concentrations of osteogenic growth factor, enhance both BMP-2 and Wnt mediated signaling in myoblasts and bone marrow stromal cells, respectively. Conversely, analogous nanostructures with enhanced levels of internal hydrogen bonding and cohesion lead to an overall reduction in BMP-2 signaling. We propose that the mechanism for enhanced growth factor signaling by the nanostructures is related to their ability to increase diffusion within membrane lipid rafts. The phenomenon reported here could lead to new nanomedicine strategies to mediate growth factor signaling for translational targets.

Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.

Science.gov (United States)

Guyot, Patricia; Ades, A E; Ouwens, Mario J N M; Welton, Nicky J

2012-02-01

The results of Randomized Controlled Trials (RCTs) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios) with statistics based on repeated reconstructions by multiple observers. The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported. The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.

E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

OpenAIRE

Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

2016-01-01

Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a ...

E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

Science.gov (United States)

Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

2016-01-01

Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

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Ha-Na Na

Full Text Available Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR, and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1. In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

Boosted TCA cycle enhances survival of zebrafish to Vibrio alginolyticus infection.

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Yang, Man-Jun; Cheng, Zhi-Xue; Jiang, Ming; Zeng, Zao-Hai; Peng, Bo; Peng, Xuan-Xian; Li, Hui

2018-01-01

Vibrio alginolyticus is a waterborne pathogen that infects a wide variety of hosts including fish and human, and the outbreak of this pathogen can cause a huge economic loss in aquaculture. Thus, enhancing host's capability to survive from V. alginolyticus infection is key to fighting infection and this remains still unexplored. In the present study, we established a V. alginolyticus-zebrafish interaction model by which we explored how zebrafish survived from V. alginolyticus infection. We used GC-MS based metabolomic approaches to characterize differential metabolomes between survival and dying zebrafish upon infection. Pattern recognition analysis identified the TCA cycle as the most impacted pathway. The metabolites in the TCA cycle were decreased in the dying host, whereas the metabolites were increased in the survival host. Furthermore, the enzymatic activities of the TCA cycle including pyruvate dehydrogenase (PDH), α-ketoglutaric dehydrogenase (KGDH) and succinate dehydrogenase (SDH) also supported this conclusion. Among the increased metabolites in the TCA cycle, malic acid was the most crucial biomarker for fish survival. Indeed, exogenous malate promoted zebrafish survival in a dose-dependent manner. The corresponding activities of KGDH and SDH were also increased. These results indicate that the TCA cycle is a key pathway responsible for the survival or death in response to infection caused by V. alginolyticus, and highlight the way on development of metabolic modulation to control the infection.

The impact of phosphatases on proliferative and survival signaling in cancer.

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Narla, Goutham; Sangodkar, Jaya; Ryder, Christopher B

2018-05-03

The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.

Deep sea minerals prolong life span of streptozotocin-induced diabetic rats by compensatory augmentation of the IGF-I-survival signaling and inhibition of apoptosis.

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Liao, Hung-En; Shibu, Marthandam Asokan; Kuo, Wei-Wen; Pai, Pei-Ying; Ho, Tsung-Jung; Kuo, Chia-Hua; Lin, Jing-Ying; Wen, Su-Ying; Viswanadha, Vijaya Padma; Huang, Chih-Yang

2016-07-01

Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia-induced myocardial hypertrophy and cardiac-apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia-induced cardiac-apoptosis that causes severe cardiac-damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio-protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg(-1) ) IP injection. Different doses of DSM-1× (37 mg kg(-1) day(-1) ), 2× (74 mg kg(-1) day(-1) ) and 3× (111 mg kg(-1) day(-1) ), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO4 . Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac-apoptosis and control cardiac-dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac-cell proliferation and by controlling cardiac-apoptosis and associated cardiac-dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769-781, 2016. © 2015 Wiley Periodicals, Inc.

Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways.

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Li, Ko-Jen; Wu, Cheng-Han; Shen, Chieh-Yu; Kuo, Yu-Min; Yu, Chia-Li; Hsieh, Song-Chou

2016-01-01

The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and

Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways.

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Ko-Jen Li

Full Text Available The biological significance of membrane transfer (trogocytosis between polymorphonuclear neutrophils (PMNs and mononuclear cells (MNCs remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE. By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059 and protein kinase C (Rottlerin. Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on

Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves

Directory of Open Access Journals (Sweden)

Guyot Patricia

2012-02-01

Full Text Available Abstract Background The results of Randomized Controlled Trials (RCTs on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios with statistics based on repeated reconstructions by multiple observers. Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported. Conclusion The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.

Multinuclear giant cell formation is enhanced by down-regulation of Wnt signaling in gastric cancer cell line, AGS

International Nuclear Information System (INIS)

Kim, Shi-Mun; Kim, Rockki; Ryu, Jae-Hyun; Jho, Eek-Hoon; Song, Ki-Joon; Jang, Shyh-Ing; Kee, Sun-Ho

2005-01-01

AGS cells, which were derived from malignant gastric adenocarcinoma tissue, lack E-cadherin-mediated cell adhesion but have a high level of nuclear β-catenin, which suggests altered Wnt signal. In addition, approximately 5% of AGS cells form multinuclear giant cells in the routine culture conditions, while taxol treatment causes most AGS cells to become giant cells. The observation of reduced nuclear β-catenin levels in giant cells induced by taxol treatment prompted us to investigate the relationship between Wnt signaling and giant cell formation. After overnight serum starvation, the shape of AGS cells became flattened, and this morphological change was accompanied by decrease in Myc expression and an increase in the giant cell population. Lithium chloride treatment, which inhibits GSK3β activity, reversed these serum starvation effects, which suggests an inverse relationship between Wnt signaling and giant cell formation. Furthermore, the down-regulation of Wnt signaling caused by the over-expression of ICAT, E-cadherin, and Axin enhanced giant cell formation. Therefore, down-regulation of Wnt signaling may be related to giant cell formation, which is considered to be a survival mechanism against induced cell death

Cell Survival Signaling in Neuroblastoma

Science.gov (United States)

Megison, Michael L.; Gillory, Lauren A.; Beierle, Elizabeth A.

2013-01-01

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID:22934706

Ehrlichia chaffeensis TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

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Taslima T. Lina

2016-07-01

Full Text Available Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40% were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2 and p38 mitogen-activated protein kinase (MAPK pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4 expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival.

Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

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Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

2009-04-01

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

Fibrin-Enhanced Canonical Wnt Signaling Directs Plasminogen Expression in Cementoblasts

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Saeed Ur Rahman

2017-11-01

Full Text Available Cementum is a mineralized layer on the tooth’s root surface and facilitates the biomechanical anchoring of fibrous connective tissues as a part of tooth-supportive complexes. Previously, we observed that OCCM30 cementoblasts cultured on fibrin matrices underwent apoptosis due to fibrin degradation through the expression of proteases. Here, we demonstrated that OCCM30 on fibrin matrices (OCCM30-fibrin enhanced canonical Wnt signaling, which directed to plasminogen expression. The OCCM30-fibrin showed higher levels of Wnt3a expression, nuclear translocation of β-catenin, and T-cell factor (TCF optimal motif (TOP reporter activity than the cells on tissue culture dishes (OCCM30-TCD, indicating that the OCCM30-fibrin enhanced canonical Wnt/β-catenin signaling. Also, OCCM30-fibrin expressed biomineralization-associated markers at higher levels than OCCM30-TCD, of which levels were further increased with LiCl, a Wnt signaling activator. The OCCM30 cementoblasts simultaneously showed that high levels of plasminogen, a critical component of fibrinolysis, were expressed in the OCCM30-fibrin. Activation of canonical Wnt signaling with LiCl treatment or with forced lymphoid enhancer factor 1 (LEF1-expression increased the expression of plasminogen. On the contrary, the inhibition of canonical Wnt signaling with siRNAs against Wnt3a or β-catenin abrogated fibrin-enhanced plasminogen expression. Furthermore, there are three conserved putative response elements for the LEF1/β-catenin complex in the plasminogen proximal promoter regions (−900 to +54. Site-directed mutations and chromatin immunoprecipitation indicated that canonical Wnt signaling directed plasminogen expression. Taken together, this study suggests that fibrin-based materials can modulate functional periodontal formations in controlling cementoblast differentiation and fibrin degradation.

Loss of Endogenous Interleukin-12 Activates Survival Signals in Ultraviolet-Exposed Mouse Skin and Skin Tumors

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Syed M. Meeran

2009-09-01

Full Text Available Interleukin-12 (IL-12-deficiency promotes photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Here, we report that long-term exposure to ultraviolet (UV radiation resulted in enhancement of the levels of cell survival kinases, such as phosphatidylinositol 3-kinase (PI3K, Akt (Ser473, p-ERK1/2, and p-p38 in the skin of IL-12p40 knockout (IL-12 KO mice compared with the skin of wild-type mice. UV-induced activation of nuclear factor-κB (NF-κB/p65 in the skin of IL-12 KO mice was also more prominent. The levels of NF-κB-targeted proteins, such as proliferating cell nuclear antigen (PCNA, cyclooxygenase-2, cyclin D1, and inducible nitric oxide synthase, were higher in the UV-exposed skin of IL-12 KO mice than the UV-exposed skin of wild types. In short-term UV irradiation experiments, subcutaneous treatment of IL-12 KO mice with recombinant IL-12 (rIL-12 or topical treatment with oridonin, an inhibitor of NF-κB, resulted in the inhibition of UV-induced increases in the levels of PCNA, cyclin D1, and NF-κB compared with non-rIL-12- or non-oridonin-treated IL-12 KO mice. UV-induced skin tumors of IL-12 KO mice had higher levels of PI3K, p-Akt (Ser473, p-ERK1/2, p-p38, NF-κB, and PCNA and fewer apoptotic cells than skin tumors of wild types. Together, these data suggest that the loss of endogenous IL-12 activates survival signals in UV-exposed skin and that may lead to the enhanced photocarcinogenesis in mice.

An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes.

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Bravo-Adame, Maria Elena; Vera-Estrella, Rosario; Barkla, Bronwyn J; Martínez-Campos, Cecilia; Flores-Alcantar, Angel; Ocelotl-Oviedo, Jose Pablo; Pedraza-Alva, Gustavo; Rosenstein, Yvonne

2017-01-01

CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y 105 of PKM2 and of Y 705 of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-κB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes. © 2016 John Wiley & Sons Ltd.

Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

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Kristen M. Drescher

2010-01-01

Full Text Available High levels of microsatellite instability (MSI-high are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients.

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Drescher, Kristen M; Sharma, Poonam; Lynch, Henry T

2010-01-01

High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor.

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Dedoni, Simona; Olianas, Maria C; Ingianni, Angela; Onali, Pierluigi

2017-04-01

Although clinically useful for the treatment of various diseases, type I interferons (IFNs) have been implicated as causative factors of a number of neuroinflammatory disorders characterized by neuronal damage and altered CNS functions. As neurotrophin 3 (NT3) plays a critical role in neuroprotection, we examined the effects of IFN-β on the signalling and functional activity of the NT3/TrkC system. We found that prolonged exposure of differentiated human SH-SY5Y neuroblastoma cells to IFN-β impaired the ability of NT3 to induce transphosphorylation of the full-length TrkC receptor (TrkC-FL) and the phosphorylation of downstream signalling molecules, including PLCγ1, Akt, GSK-3β and ERK1/2. NT3 was effective in protecting the cells against apoptosis triggered by serum withdrawal or thapsigargin but not IFN-β. Prolonged exposure to the cytokine had little effects on TrkC-FL levels but markedly enhanced the messenger RNA (mRNA) and protein levels of the truncated isoform TrkC-T1, a dominant-negative receptor that inhibits TrkC-FL activity. Cell depletion of TrkC-T1 by small interfering RNA (siRNA) treatment enhanced NT3 signalling through TrkC-FL and allowed the neurotrophin to counteract IFN-β-induced apoptosis. Furthermore, the upregulation of TrkC-T1 by IFN-β was associated with the inhibition of NT3-induced recruitment of the scaffold protein tamalin to TrkC-T1 and tamalin tyrosine phosphorylation. These data indicate that IFN-β exerts a negative control on NT3 pro-survival signalling through a novel mechanism involving the upregulation of TrkC-T1.

Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery.

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Zolal, Amir; Juratli, Tareq A; Linn, Jennifer; Podlesek, Dino; Sitoci Ficici, Kerim Hakan; Kitzler, Hagen H; Schackert, Gabriele; Sobottka, Stephan B; Rieger, Bernhard; Krex, Dietmar

2016-05-01

Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis.

Enhancement of speech signals - with a focus on voiced speech models

DEFF Research Database (Denmark)

Nørholm, Sidsel Marie

This thesis deals with speech enhancement, i.e., noise reduction in speech signals. This has applications in, e.g., hearing aids and teleconference systems. We consider a signal-driven approach to speech enhancement where a model of the speech is assumed and filters are generated based...... on this model. The basic model used in this thesis is the harmonic model which is a commonly used model for describing the voiced part of the speech signal. We show that it can be beneficial to extend the model to take inharmonicities or the non-stationarity of speech into account. Extending the model...

Rapidity gap survival in enhanced Pomeron scheme

Energy Technology Data Exchange (ETDEWEB)

Ostapchenko, Sergey [Frankfurt Institute for Advanced Studies, Frankfurt am Main (Germany); Moscow State University, D.V. Skobeltsyn Institute of Nuclear Physics, Moscow (Russian Federation); Bleicher, Marcus [Frankfurt Institute for Advanced Studies, Frankfurt am Main (Germany); Goethe-Universitat, Institute for Theoretical Physics, Frankfurt am Main (Germany)

2018-01-15

We apply the phenomenological Reggeon field theory framework to investigate rapidity gap survival (RGS) probability for diffractive dijet production in proton-proton collisions. In particular, we study in some detail rapidity gap suppression due to elastic rescatterings of intermediate partons in the underlying parton cascades, described by enhanced (Pomeron-Pomeron interaction) diagrams. We demonstrate that such contributions play a subdominant role, compared to the usual, so-called ''eikonal'', rapidity gap suppression due to elastic rescatterings of constituent partons of the colliding protons. On the other hand, the overall RGS factor proves to be sensitive to color fluctuations in the proton. Hence, experimental data on diffractive dijet production can be used to constrain the respective model approaches. (orig.)

Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling.

Directory of Open Access Journals (Sweden)

Md Shamim Hossain

Full Text Available Neuronal cells are susceptible to many stresses, which will cause the apoptosis and neurodegenerative diseases. The precise molecular mechanism behind the neuronal protection against these apoptotic stimuli is necessary for drug discovery. In the present study, we have found that plasmalogens (Pls, which are glycerophospholipids containing vinyl ether linkage at sn-1 position, can protect the neuronal cell death upon serum deprivation. Interestingly, caspse-9, but not caspase-8 and caspase-12, was cleaved upon the serum starvation in Neuro-2A cells. Pls treatments effectively reduced the activation of caspase-9. Furthermore, cellular signaling experiments showed that Pls enhanced phosphorylation of the phosphoinositide 3-kinase (PI3K-dependent serine/threonine-specific protein kinase AKT and extracellular-signal-regulated kinases ERK1/2. PI3K/AKT inhibitor LY294002 and MAPK/ERK kinase (MEK inhibitor U0126 treatments study clearly indicated that Pls-mediated cell survival was dependent on the activation of these kinases. In addition, Pls also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation, which was associated with the inhibition of caspase-9 and caspase-3 cleavages. It was reported that Pls content decreased in the brain of the Alzheimer's patients, which indicated that the reduction of Pls content could endanger neurons. The present findings, taken together, suggest that Pls have an anti-apoptotic action in the brain. Further studies on precise mechanisms of Pls-mediated protection against cell death may lead us to establish a novel therapeutic approach to cure neurodegenerative disorders.

Stromal Adipocyte Enhancer-binding Protein (AEBP1) Promotes Mammary Epithelial Cell Hyperplasia via Proinflammatory and Hedgehog Signaling*

Science.gov (United States)

Holloway, Ryan W.; Bogachev, Oleg; Bharadwaj, Alamelu G.; McCluskey, Greg D.; Majdalawieh, Amin F.; Zhang, Lei; Ro, Hyo-Sung

2012-01-01

Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1TG) mice, and the onset of ductal hyperplasia was accelerated in AEBP1TG mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1TG bone marrow cells into non-transgenic (AEBP1NT) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1TG mammary macrophages and epithelium. Shh expression was induced in AEBP1TG macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1TG mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1TG peritoneal macrophages. The conditioned AEBP1TG macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1TG macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis. PMID:22995915

Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.

Science.gov (United States)

Holloway, Ryan W; Bogachev, Oleg; Bharadwaj, Alamelu G; McCluskey, Greg D; Majdalawieh, Amin F; Zhang, Lei; Ro, Hyo-Sung

2012-11-09

Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1(TG)) mice, and the onset of ductal hyperplasia was accelerated in AEBP1(TG) mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1(TG) bone marrow cells into non-transgenic (AEBP1(NT)) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1(TG) mammary macrophages and epithelium. Shh expression was induced in AEBP1(TG) macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1(TG) mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1(TG) peritoneal macrophages. The conditioned AEBP1(TG) macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1(TG) macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis.

Inhibition of TGF-β Signaling in SHED Enhances Endothelial Differentiation.

Science.gov (United States)

Xu, J G; Gong, T; Wang, Y Y; Zou, T; Heng, B C; Yang, Y Q; Zhang, C F

2018-02-01

Low efficiency of deriving endothelial cells (ECs) from adult stem cells hampers their utilization in tissue engineering studies. The purpose of this study was to investigate whether suppression of transforming growth factor beta (TGF-β) signaling could enhance the differentiation efficiency of dental pulp-derived stem cells into ECs. We initially used vascular endothelial growth factor A (VEGF-A) to stimulate 2 dental pulp-derived stem cells (dental pulp stem cells and stem cells from human exfoliated deciduous teeth [SHED]) and compared their differentiation capacity into ECs. We further evaluated whether the vascular endothelial growth factor receptor I (VEGF-RI)-specific ligand placental growth factor-1 (PlGF-1) could mediate endothelial differentiation. Finally, we investigated whether the TGF-β signaling inhibitor SB-431542 could enhance the inductive effect of VEGF-A on endothelial differentiation, as well as the underlying mechanisms involved. ECs differentiated from dental pulp-derived stem cells exhibited the typical phenotypes of primary ECs, with SHED possessing a higher endothelial differentiation potential than dental pulp stem cells. VEGFR1-specific ligand-PLGF exerted a negligible effect on SHED-ECs differentiation. Compared with VEGF-A alone, the combination of VEGF-A and SB-431542 significantly enhanced the endothelial differentiation of SHED. The presence of SB-431542 inhibited the phosphorylation of Suppressor of Mothers Against Decapentaplegic 2/3 (SMAD2/3), allowing for VEGF-A-dependent phosphorylation and upregulation of VEGFR2. Our results indicate that the combination of VEGF-A and SB-431542 could enhance the differentiation of dental pulp-derived stem cells into endothelial cells, and this process is mediated through enhancement of VEGF-A-VEGFR2 signaling and concomitant inhibition of TGF-β-SMAD2/3 signaling.

Analysis of Enhanced Velocity Signals Observed during Solar Flares ...

Indian Academy of Sciences (India)

2003-10-28

Oct 28, 2003 ... close to the vicinity of the hard X-ray source regions as observed with. RHESSI. The power maps of the active region show enhancement in the frequency regime 5–6.5mHz, while there is feeble or no enhancement of these signals in 2–4 mHz frequency band. High energy particles with sufficient momentum ...

Enhancement of Chiroptical Signals by Circular Differential Mie Scattering of Nanoparticles.

Science.gov (United States)

Yoo, SeokJae; Park, Q-Han

2015-09-25

We enhance the weak optical signals of small chiral molecules via circular differential Mie scattering (CDMS) of nanoparticles immersed in them. CDMS is the preferential Mie scattering of left- and right-handed circularly polarized light by nanoparticles whose sizes are about the same as the wavelength of light. Solving the Mie scattering theory for chiral media, we find that the CDMS signal of the particle is linearly proportional to the chirality parameter κ of the molecules. This linear amplitude enhancement by CDMS of the particle holds, even for large particles, which have a retardation effect. We also demonstrate that the CDMS of a nanoparticle is sensitive to changes of molecular concentration, and that the nanoparticle can be utilized as a chiroptical biosensor detecting the concentration of analyte. We expect that the enhancement of molecular chiroptical signals by CDMS will pave the way for novel chiroptical spectroscopy using nanostructures.

Mycobacterium tuberculosis Rv3402c enhances mycobacterial survival within macrophages and modulates the host pro-inflammatory cytokines production via NF-kappa B/ERK/p38 signaling.

Directory of Open Access Journals (Sweden)

Wu Li

Full Text Available Intracellular survival plays a central role in the pathogenesis of Mycobacterium tuberculosis, a process which depends on an array of virulence factors to colonize and replicate within the host. The M. tuberculosis iron regulated open reading frame (ORF rv3402c, encoding a conserved hypothetical protein, was shown to be up-regulated upon infection in both human and mice macrophages. To explore the function of this ORF, we heterologously expressed the rv3402c gene in the non-pathogenic fast-growing Mycobacterium smegmatis strain, and demonstrated that Rv3402c, a cell envelope-associated protein, was able to enhance the intracellular survival of recombinant M. smegmatis. Enhanced growth was not found to be the result of an increased resistance to intracellular stresses, as growth of the Rv3402c expressing strain was unaffected by iron depletion, H2O2 exposure, or acidic conditions. Colonization of macrophages by M. smegmatis expressing Rv3402c was associated with substantial cell death and significantly greater amount of TNF-α and IL-1β compared with controls. Rv3402c-induced TNF-α and IL-1β production was found to be mediated by NF-κB, ERK and p38 pathway in macrophages. In summary, our study suggests that Rv3402c delivered in a live M. smegmatis vehicle can modify the cytokines profile of macrophage, promote host cell death and enhance the persistence of mycobacterium within host cells.

PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication.

Science.gov (United States)

Hou, Jiun-Nan; Chen, Tien-Huang; Chiang, Yi-Hsuan; Peng, Jing-Yun; Yang, Tsong-Han; Cheng, Chih-Chieh; Sofiyatun, Eny; Chiu, Cheng-Hsun; Chiang-Ni, Chuan; Chen, Wei-June

2017-09-20

Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5'-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells. This suggests that most mosquito proteins are synthesized via canonical cap-dependent translation. When the PERK signal pathway was inhibited, both accumulation of reactive oxygen species and changes in the mitochondrial membrane potential increased. This suggested that ER stress response was alleviated through the PERK-mediated shutdown of global proteins in DENV2-infected C6/36 cells. In the meantime, the activities of caspases-9 and -3 and the apoptosis-related cell death rate increased in C6/36 cells with PERK inhibition. This reflected that the PERK-signaling pathway is involved in determining cell survival, presumably by reducing DENV2-induced ER stress. Looking at the PERK downstream target, α-subunit of eukaryotic initiation factor 2 (eIF2α), an increased phosphorylation status was only shown in infected C6/36 cells. This indicated that recruitment of ribosome binding to the mRNA 5'-cap structure could have been impaired in cap-dependent translation. It turned out that shutdown of cellular protein translation resulted in a pro-survival effect on mosquito cells in response to DENV2 infection. As synthesis of viral proteins was not affected by the PERK signal pathway, an alternate mode other than cap-dependent translation may be utilized. This finding provides insights into elucidating how the PERK signal

Picturing survival memories: enhanced memory after fitness-relevant processing occurs for verbal and visual stimuli.

Science.gov (United States)

Otgaar, Henry; Smeets, Tom; van Bergen, Saskia

2010-01-01

Recent studies have shown that processing words according to a survival scenario leads to superior retention relative to control conditions. Here, we examined whether a survival recall advantage could be elicited by using pictures. Furthermore, in Experiment 1, we were interested in whether survival processing also results in improved memory for details. Undergraduates rated the relevance of pictures in a survival, moving, or pleasantness scenario and were subsequently given a surprise free recall test. We found that survival processing yielded superior retention. We also found that distortions occurred more often in the survival condition than in the pleasantness condition. In Experiment 2, we directly compared the survival recall effect between pictures and words. A comparable survival recall advantage was found for pictures and words. The present findings support the idea that memory is enhanced by processing information in terms of fitness value, yet at the same time, the present results suggest that this may increase the risk for memory distortions.

MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal

Energy Technology Data Exchange (ETDEWEB)

Shi, Xue-Feng [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Respiration, Qinghai Provincial People' s Hospital, Xining (China); Wang, Hua; Xiao, Feng-Jun [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Yin, Yue [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Hematology, Peking University First Hospital, Beijing (China); Xu, Qin-Qin [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Ge, Ri-Li, E-mail: geriligao@hotmail.com [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Wang, Li-Sheng, E-mail: wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China)

2016-02-12

MicroRNA-486 (miR-486) was first identified from human fetal liver cDNA library and validated as a regulator of hematopoiesis. Its roles in regulating the biological function of bone marrow-derived mesnechymal stem cells (BM-MSCs) under hypoxia have not been explored yet. In this study, we demonstrated that exposure to hypoxia upregulates miR-486 expression in BM-MSCs. Lentivirus-mediated overexpression of miR-486 resulted in increase of hepatocyte growth factor (HGF) and vascular endothelial growth factor(VEGF) in both mRNA and protein levels. MiR-486 expression also promotes proliferation and reduces apoptosis of BM-MSCs. Whereas MiR-486 knockdown downregulated the secretion of HGF and VEGF and induced apoptosis of BM-MSCs. Furthermore, PTEN-PI3K/AKT signaling was validated to be involved in changes of BM-MSC biological functions regulated by miR-486. These results suggested that MiR-486 mediated the hypoxia-induced angiogenic activity and promoted the proliferation and survival of BM-MSCs through regulating PTEN-PI3K/AKT signaling. These findings might provide a novel understanding of effective therapeutic strategy for hypoxic-ischemic diseases. - Highlights: • miR-486 is a hypoxia-induced miRNA. • miR-486 regulates the secretion of HGF and VEGF, promotes proliferation, and inhibits apoptosis of BM-MSCs. • miR-486 enhances PI3K/AKT activity signaling by targeting PTEN molecule.

Dragon enhances BMP signaling and increases transepithelial resistance in kidney epithelial cells.

Science.gov (United States)

Xia, Yin; Babitt, Jodie L; Bouley, Richard; Zhang, Ying; Da Silva, Nicolas; Chen, Shanzhuo; Zhuang, Zhenjie; Samad, Tarek A; Brenner, Gary J; Anderson, Jennifer L; Hong, Charles C; Schneyer, Alan L; Brown, Dennis; Lin, Herbert Y

2010-04-01

The neuronal adhesion protein Dragon acts as a bone morphogenetic protein (BMP) coreceptor that enhances BMP signaling. Given the importance of BMP signaling in nephrogenesis and its putative role in the response to injury in the adult kidney, we studied the localization and function of Dragon in the kidney. We observed that Dragon localized predominantly to the apical surfaces of tubular epithelial cells in the thick ascending limbs, distal convoluted tubules, and collecting ducts of mice. Dragon expression was weak in the proximal tubules and glomeruli. In mouse inner medullary collecting duct (mIMCD3) cells, Dragon generated BMP signals in a ligand-dependent manner, and BMP4 is the predominant endogenous ligand for the Dragon coreceptor. In mIMCD3 cells, BMP4 normally signaled through BMPRII, but Dragon enhanced its signaling through the BMP type II receptor ActRIIA. Dragon and BMP4 increased transepithelial resistance (TER) through the Smad1/5/8 pathway. In epithelial cells isolated from the proximal tubule and intercalated cells of collecting ducts, we observed coexpression of ActRIIA, Dragon, and BMP4 but not BMPRII. Taken together, these results suggest that Dragon may enhance BMP signaling in renal tubular epithelial cells and maintain normal renal physiology.

Protein sensing by nanofluidic crystal and its signal enhancement

Science.gov (United States)

Sang, Jianming; Du, Hongtan; Wang, Wei; Chu, Ming; Wang, Yuedan; Li, Haichao; Alice Zhang, Haixia; Wu, Wengang; Li, Zhihong

2013-01-01

Nanofluidics has a unique property that ionic conductance across a nanometer-sized confined space is strongly affected by the space surface charge density, which can be utilized to construct electrical read-out biosensor. Based on this principle, this work demonstrated a novel protein sensor along with a sandwich signal enhancement approach. Nanoparticles with designed aptamer onside are assembled in a suspended micropore to form a 3-dimensional network of nanometer-sized interstices, named as nanofluidic crystal hereafter, as the basic sensing unit. Proteins captured by aptamers will change the surface charge density of nanoparticles and thereby can be detected by monitoring the ionic conductance across this nanofluidic crystal. Another aptamer can further enlarge the variations of the surface charge density by forming a sandwich structure (capturing aptamer/protein/signal enhancement aptamer) and the read-out conductance as well. The preliminary experimental results indicated that human α-thrombin was successfully detected by the corresponding aptamer modified nanofluidic crystal with the limit of detection of 5 nM (0.18 μg/ml) and the read-out signal was enhanced up to 3 folds by using another thrombin aptamer. Being easy to graft probe, facile and low-cost to prepare the nano-device, and having an electrical read-out, the present nanofluidic crystal scheme is a promising and universal strategy for protein sensing. PMID:24404017

period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection.

Science.gov (United States)

Allen, Victoria W; O'Connor, Reed M; Ulgherait, Matthew; Zhou, Clarice G; Stone, Elizabeth F; Hill, Vanessa M; Murphy, Keith R; Canman, Julie C; Ja, William W; Shirasu-Hiza, Mimi M

2016-01-25

Most metazoans undergo dynamic, circadian-regulated changes in behavior and physiology. Currently, it is unknown how circadian-regulated behavior impacts immunity against infection. Two broad categories of defense against bacterial infection are resistance, control of microbial growth, and tolerance, control of the pathogenic effects of infection. Our study of behaviorally arrhythmic Drosophila circadian period mutants identified a novel link between nutrient intake and tolerance of infection with B. cepacia, a bacterial pathogen of rising importance in hospital-acquired infections. We found that infection tolerance in wild-type animals is stimulated by acute exposure to dietary glucose and amino acids. Glucose-stimulated tolerance was induced by feeding or direct injection; injections revealed a narrow window for glucose-stimulated tolerance. In contrast, amino acids stimulated tolerance only when ingested. We investigated the role of a known amino-acid-sensing pathway, the TOR (Target of Rapamycin) pathway, in immunity. TORC1 is circadian regulated and inhibition of TORC1 decreased resistance, as in vertebrates. Surprisingly, inhibition of the less well-characterized TOR complex 2 (TORC2) dramatically increased survival, through both resistance and tolerance mechanisms. This work suggests that dietary intake on the day of infection by B. cepacia can make a significant difference in long-term survival. We further demonstrate that TOR signaling mediates both resistance and tolerance of infection and identify TORC2 as a novel potential therapeutic target for increasing survival of infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Survival Processing Enhances Visual Search Efficiency.

Science.gov (United States)

Cho, Kit W

2018-05-01

Words rated for their survival relevance are remembered better than when rated using other well-known memory mnemonics. This finding, which is known as the survival advantage effect and has been replicated in many studies, suggests that our memory systems are molded by natural selection pressures. In two experiments, the present study used a visual search task to examine whether there is likewise a survival advantage for our visual systems. Participants rated words for their survival relevance or for their pleasantness before locating that object's picture in a search array with 8 or 16 objects. Although there was no difference in search times among the two rating scenarios when set size was 8, survival processing reduced visual search times when set size was 16. These findings reflect a search efficiency effect and suggest that similar to our memory systems, our visual systems are also tuned toward self-preservation.

PKC-η-MARCKS Signaling Promotes Intracellular Survival of Unopsonized Burkholderia thailandensis.

Science.gov (United States)

Micheva-Viteva, Sofiya N; Shou, Yulin; Ganguly, Kumkum; Wu, Terry H; Hong-Geller, Elizabeth

2017-01-01

Pathogenic Burkholderia rely on host factors for efficient intracellular replication and are highly refractory to antibiotic treatment. To identify host genes that are required by Burkholderia spp. during infection, we performed a RNA interference (RNAi) screen of the human kinome and identified 35 host kinases that facilitated Burkholderia thailandensis intracellular survival in human monocytic THP-1 cells. We validated a selection of host kinases using imaging flow cytometry to assess efficiency of B. thailandensis survival in the host upon siRNA-mediated knockdown. We focused on the role of the novel protein kinase C isoform, PKC-η, in Burkholderia infection and characterized PKC-η/MARCKS signaling as a key event that promotes the survival of unopsonized B. thailandensis CDC2721121 within host cells. While infection of lung epithelial cells with unopsonized Gram-negative bacteria stimulated phosphorylation of Ser175/160 in the MARCKS effector domain, siRNA-mediated knockdown of PKC-η expression reduced the levels of phosphorylated MARCKS by >3-fold in response to infection with Bt CDC2721121. We compared the effect of the conventional PKC-α and novel PKC-η isoforms on the growth of B. thailandensis CDC2721121 within monocytic THP-1 cells and found that ≥75% knock-down of PRKCH transcript levels reduced intracellular bacterial load 100% more efficiently when compared to growth in cells siRNA-depleted of the classical PKC-α, suggesting that the PKC-η isoform can specifically mediate Burkholderia intracellular survival. Based on imaging studies of intracellular B. thailandensis , we found that PKC-η function stimulates phagocytic pathways that promote B. thailandensis escape into the cytoplasm leading to activation of autophagosome flux. Identification of host kinases that are targeted by Burkholderia during infection provides valuable molecular insights in understanding Burkholderia pathogenesis, and ultimately, in designing effective host

Improved stochastic resonance algorithm for enhancement of signal-to-noise ratio of high-performance liquid chromatographic signal

International Nuclear Information System (INIS)

Xie Shaofei; Xiang Bingren; Deng Haishan; Xiang Suyun; Lu Jun

2007-01-01

Based on the theory of stochastic resonance, an improved stochastic resonance algorithm with a new criterion for optimizing system parameters to enhance signal-to-noise ratio (SNR) of HPLC/UV chromatographic signal for trace analysis was presented in this study. Compared with the conventional criterion in stochastic resonance, the proposed one can ensure satisfactory SNR as well as good peak shape of chromatographic peak in output signal. Application of the criterion to experimental weak signals of HPLC/UV was investigated and the results showed an excellent quantitative relationship between different concentrations and responses

Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.

Science.gov (United States)

Tiong, Kai Hung; Tan, Boon Shing; Choo, Heng Lungh; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Tan, Si Hoey; Khor, Nelson Tze Woei; Wong, Shew Fung; See, Sze-Jia; Tan, Yuen-Fen; Rosli, Rozita; Cheong, Soon-Keng; Leong, Chee-Onn

2016-09-06

Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.

Hedgehog Signaling Regulates the Survival of Gastric Cancer Cells by Regulating the Expression of Bcl-2

Science.gov (United States)

Han, Myoung-Eun; Lee, Young-Suk; Baek, Sun-Yong; Kim, Bong-Seon; Kim, Jae-Bong; Oh, Sae-Ock

2009-01-01

Gastric cancer is the second most common cause of cancer deaths worldwide. The underlying molecular mechanisms of its carcinogenesis are relatively poorly characterized. Hedgehog (Hh) signaling, which is critical for development of various organs including the gastrointestinal tract, has been associated with gastric cancer. The present study was undertaken to reveal the underlying mechanism by which Hh signaling controls gastric cancer cell proliferation. Treatment of gastric cancer cells with cyclopamine, a specific inhibitor of Hh signaling pathway, reduced proliferation and induced apoptosis of gastric cancer cells. Cyclopamine treatment induced cytochrome c release from mitochondria and cleavage of caspase 9. Moreover, Bcl-2 expression was significantly reduced by cyclopamine treatment. These results suggest that Hh signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2. PMID:19742123

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes*

Science.gov (United States)

Collins, John A.; Wood, Scott T.; Nelson, Kimberly J.; Rowe, Meredith A.; Carlson, Cathy S.; Chubinskaya, Susan; Poole, Leslie B.; Furdui, Cristina M.; Loeser, Richard F.

2016-01-01

Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1–3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism. PMID:26797130

A TRPV channel modulates C. elegans neurosecretion, larval starvation survival, and adult lifespan.

Directory of Open Access Journals (Sweden)

Brian H Lee

2008-10-01

Full Text Available For most organisms, food is only intermittently available; therefore, molecular mechanisms that couple sensation of nutrient availability to growth and development are critical for survival. These mechanisms, however, remain poorly defined. In the absence of nutrients, newly hatched first larval (L1 stage Caenorhabditis elegans halt development and survive in this state for several weeks. We isolated mutations in unc-31, encoding a calcium-activated regulator of neural dense-core vesicle release, which conferred enhanced starvation survival. This extended survival was reminiscent of that seen in daf-2 insulin-signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling. While insulin signaling modulates metabolism, adult lifespan, and dauer formation, insulin-independent mechanisms that also regulate these processes did not promote starvation survival, indicating that regulation of starvation survival is a distinct program. Cell-specific rescue experiments identified a small subset of primary sensory neurons where unc-31 reconstitution modulated starvation survival, suggesting that these neurons mediate perception of food availability. We found that OCR-2, a transient receptor potential vanilloid (TRPV channel that localizes to the cilia of this subset of neurons, regulates peptide-hormone secretion and L1 starvation survival. Moreover, inactivation of ocr-2 caused a significant extension in adult lifespan. These findings indicate that TRPV channels, which mediate sensation of diverse noxious, thermal, osmotic, and mechanical stimuli, couple nutrient availability to larval starvation survival and adult lifespan through modulation of neural dense-core vesicle secretion.

Rapid Nanoprobe Signal Enhancement by In Situ Gold Nanoparticle Synthesis.

Science.gov (United States)

Dias, Jorge T; Svedberg, Gustav; Nystrand, Mats; Andersson-Svahn, Helene; Gantelius, Jesper

2018-03-07

The use of nanoprobes such as gold, silver, silica or iron-oxide nanoparticles as detection reagents in bioanalytical assays can enable high sensitivity and convenient colorimetric readout. However, high densities of nanoparticles are typically needed for detection. The available synthesis-based enhancement protocols are either limited to gold and silver nanoparticles or rely on precise enzymatic control and optimization. Here, we present a protocol to enhance the colorimetric readout of gold, silver, silica, and iron oxide nanoprobes. It was observed that the colorimetric signal can be improved by up to a 10000-fold factor. The basis for such signal enhancement strategies is the chemical reduction of Au 3+ to Au 0 . There are several chemical reactions that enable the reduction of Au 3+ to Au 0 . In the protocol, Good's buffers and H2O2 are used and it is possible to favor the deposition of Au 0 onto the surface of existing nanoprobes, in detriment of the formation of new gold nanoparticles. The protocol consists of the incubation of the microarray with a solution consisting of chloroauric acid and H2O2 in 2-(N-morpholino)ethanesulfonic acid pH 6 buffer following the nanoprobe-based detection assay. The enhancement solution can be applied to paper and glass-based sensors. Moreover, it can be used in commercially available immunoassays as demonstrated by the application of the method to a commercial allergen microarray. The signal development requires less than 5 min of incubation with the enhancement solution and the readout can be assessed by naked eye or low-end image acquisition devices such as a table-top scanner or a digital camera.

Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival

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Schultz Chad R

2012-04-01

Full Text Available Abstract Background The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ, followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Results Our studies found the following. 1 SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2 Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3 Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4 Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5 However, inhibiting pAKT suppresses tumor cell survival. 6 Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7 There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8 This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1 SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2 Despite this enhanced signaling, SPARC protects cells against TMZ. 3 This protection can be reduced

Does a trade-off between current reproductive success and survival affect the honesty of male signalling in species with male parental care?

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Kelly, N B; Alonzo, S H

2010-11-01

Recent theory predicted that male advertisement will reliably signal investment in paternal care in species where offspring survival requires paternal care and males allocate resources between advertisement and care. However, the predicted relationship between care and advertisement depended on the marginal gains from investment in current reproductive traits. Life history theory suggests that these fitness gains are also subject to a trade-off between current and future reproduction. Here, we investigate whether male signalling remains a reliable indicator of parental care when males allocate resources between current advertisement, paternal care and survival to future reproduction. We find that advertisement is predicted to remain a reliable signal of male care but that advertisement may cease to reliably indicate male quality because low-quality males are predicted to invest in current reproduction, whereas higher-quality males are able to invest in both current reproduction and survival to future reproduction. © 2010 The Authors. Journal Compilation © 2010 European Society For Evolutionary Biology.

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

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Yi Liu

2017-04-01

Full Text Available Summary: Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC function. Latexin (Lxn is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit. : In this article, Liang and colleagues show that loss of latexin in vivo expands the HSC population and increases their survival and engraftment. Latexin regulates HSC function and hematopoiesis via the Thbs1 signaling pathway. Keywords: latexin, hematopoietic stem cell, repopulating advantage, expansion, survival, thrombospondin 1

Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-κB-mediated survival signaling

International Nuclear Information System (INIS)

Leskinen, Markus J.; Heikkilae, Hanna M.; Speer, Mei Y.; Hakala, Jukka K.; Laine, Mika; Kovanen, Petri T.; Lindstedt, Ken A.

2006-01-01

Chymase released from activated mast cells induces apoptosis of vascular smooth muscle cells (SMCs) in vitro by degrading the pericellular matrix component fibronectin, so causing disruption of focal adhesion complexes and Akt dephosphorylation, which are necessary for cell adhesion and survival. However, the molecular mechanisms of chymase-mediated apoptosis downstream of Akt have remained elusive. Here, we show by means of RT-PCR, Western blotting, EMSA, immunocytochemistry and confocal microscopy, that chymase induces SMC apoptosis by disrupting NF-κB-mediated survival signaling. Following chymase treatment, the translocation of active NF-κB/p65 to the nucleus was partly abolished and the amount of nuclear p65 was reduced. Pretreatment of SMCs with chymase also inhibited LPS- and IL-1β-induced nuclear translocation of p65. The chymase-induced degradation of p65 was mediated by active caspases. Loss of NF-κB-mediated transactivation resulted in downregulation of bcl-2 mRNA and protein expression, leading to mitochondrial swelling and release of cytochrome c. The apoptotic process involved activation of both caspase 9 and caspase 8. The results reveal that, by disrupting the NF-κB-mediated survival-signaling pathway, activated chymase-secreting mast cells can mediate apoptosis of cultured arterial SMCs. Since activated mast cells colocalize with apoptotic SMCs in vulnerable areas of human atherosclerotic plaques, they may participate in the weakening and rupture of atherosclerotic plaques

Protein Translation and Signaling in Human Eosinophils

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Stephane Esnault

2017-09-01

Full Text Available We have recently reported that, unlike IL-5 and GM-CSF, IL-3 induces increased translation of a subset of mRNAs. In addition, we have demonstrated that Pin1 controls the activity of mRNA binding proteins, leading to enhanced mRNA stability, GM-CSF protein production and prolonged eosinophil (EOS survival. In this review, discussion will include an overview of cap-dependent protein translation and its regulation by intracellular signaling pathways. We will address the more general process of mRNA post-transcriptional regulation, especially regarding mRNA binding proteins, which are critical effectors of protein translation. Furthermore, we will focus on (1 the roles of IL-3-driven sustained signaling on enhanced protein translation in EOS, (2 the mechanisms regulating mRNA binding proteins activity in EOS, and (3 the potential targeting of IL-3 signaling and the signaling leading to mRNA binding activity changes to identify therapeutic targets to treat EOS-associated diseases.

Enhancing Raman signals with an interferometrically controlled AFM tip

International Nuclear Information System (INIS)

Oron-Carl, Matti; Krupke, Ralph

2013-01-01

We demonstrate the upgrade of a commercial confocal Raman microscope into a tip-enhanced Raman microscope/spectroscopy system (TERS) by integrating an interferometrically controlled atomic force microscope into the base of an existing upright microscope to provide near-field detection and thus signal enhancement. The feasibility of the system is demonstrated by measuring the Raman near-field enhancement on thin PEDOT:PSS films and on carbon nanotubes within a device geometry. An enhancement factor of 2–3 and of 5–6 is observed, respectively. Moreover, on a nanotube device we show local conductivity measurement and its correlation to Raman and topography recordings. Upgrading an existing upright confocal Raman microscope in the demonstrated way is significantly cheaper than purchasing a complete commercial TERS system. (paper)

Female partner preferences enhance offspring ability to survive an infection.

Science.gov (United States)

Raveh, Shirley; Sutalo, Sanja; Thonhauser, Kerstin E; Thoß, Michaela; Hettyey, Attila; Winkelser, Friederike; Penn, Dustin J

2014-01-23

It is often suggested that mate choice enhances offspring immune resistance to infectious diseases. To test this hypothesis, we conducted a study with wild-derived house mice (Mus musculus musculus) in which females were experimentally mated either with their preferred or non-preferred male, and their offspring were infected with a mouse pathogen, Salmonella enterica (serovar Typhimurium). We found that offspring sired by preferred males were significantly more likely to survive the experimental infection compared to those sired by non-preferred males. We found no significant differences in the pathogen clearance or infection dynamics between the infected mice, suggesting that offspring from preferred males were better able to cope with infection and had improved tolerance rather than immune resistance. Our results provide the first direct experimental evidence within a single study that partner preferences enhance offspring resistance to infectious diseases.

Born to be Alive: A Role for the BCL-2 Family in Melanoma Tumor Cell Survival, Apoptosis, and Treatment

Energy Technology Data Exchange (ETDEWEB)

Anvekar, Rina A.; Asciolla, James J.; Missert, Derek J.; Chipuk, Jerry E., E-mail: jerry.chipuk@mssm.edu [Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY (United States); Department of Dermatology, Mount Sinai School of Medicine, New York, NY (United States); The Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY (United States)

2011-10-13

The global incidence of melanoma has dramatically increased during the recent decades, yet the advancement of primary and adjuvant therapies has not kept a similar pace. The development of melanoma is often centered on cellular signaling that hyper-activates survival pathways, while inducing a concomitant blockade to cell death. Aberrations in cell death signaling not only promote tumor survival and enhanced metastatic potential, but also create resistance to anti-tumor strategies. Chemotherapeutic agents target melanoma tumor cells by inducing a form of cell death called apoptosis, which is governed by the BCL-2 family of proteins. The BCL-2 family is comprised of anti-apoptotic proteins (e.g., BCL-2, BCL-xL, and MCL-1) and pro-apoptotic proteins (e.g., BAK, BAX, and BIM), and their coordinated regulation and function are essential for optimal responses to chemotherapeutics. Here we will discuss what is currently known about the mechanisms of BCL-2 family function with a focus on the signaling pathways that maintain melanoma tumor cell survival. Importantly, we will critically evaluate the literature regarding how chemotherapeutic strategies directly impact on BCL-2 family function and offer several suggestions for future regimens to target melanoma and enhance patient survival.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody, C225, enhances radiation-induced apoptosis in primary glioma cell lines through mediation of MAPK/JNK/p38 signaling pathways

International Nuclear Information System (INIS)

Chakravarti, A.; Noll, E.; Black, P.M.; Loeffler, J.S.

2001-01-01

Purpose: Increasing evidence suggests that signaling mediated by the epidermal growth factor receptor (EGFR) pathway contributes to radiation resistance. The anti-EGFR monoclonal antibody, C225, has been shown to enhance radiation response for several tumor types in preclinical models. Malignant gliomas are known to express, and quite frequently overexpress, EGFR. Our objectives in this study were to 1) Evaluate the efficacy of C225 as a radiation response modifier in EGFR-expressing glioma cell lines and to 2) Investigate the underlying molecular mechanisms mediating C225-induced enhancement of radiation response. Materials and Methods: Twelve EGFR-expressing glioma cells lines, established from patient tumors, were used for this study. Cells were incubated with C225, irradiated, and then evaluated for radiation response. Assays used to evaluate efficacy of C225-mediated radiosensitization included time-course apoptosis assays (Annexin V and TUNEL), viability assays (MTT), and clonogenic survival assays. The changes along MAPK (p44/p42)/JNK/p38-MAPK signal transduction pathways were then investigated using quantitative Western analysis with phospho-specific antibodies to determine the molecular mechanisms by which C225 mediates a given response. Results: C225 clearly enhanced radiation response for 7 of the 12 primary glioma cell lines studied. Enhancement of both immediate and delayed apoptotic responses was evident in these 7 responsive cell lines after C225 administration. The average apoptosis index at 6 hours post-RT+C225 for the 7 responsive lines was 9.5%, compared to 1.2% for the RT-only controls. A pattern of delayed apoptosis was evident in these 7 lines, with secondary apoptotic peaks (∼ 8.0%) occurring at 24 hours post-RT+C225. Time course viability measurements revealed a steady decrease in viable tumor cells in these responsive cell lines from 75% at 6 hours post-RT+C225 to 20% at 7 days. Clonogenic survival was also diminished in these 7 lines

Stem cell factor enhances the survival of murine intestinal stem cells after photon irradiation

International Nuclear Information System (INIS)

Leigh, B.R.; Khan, W.; Hancock, S.L.

1995-01-01

Recombinant rat stem cell factor (SCF) has been shown to decrease lethality in mice exposed to total-body irradiation (TBI) in the lower range of lethality through radioprotection of hematopoietic stem cells and acceleration of bone marrow repopulation. This study evaluates the effect of SCF on the survival of the intestinal mucosal stem cell after TBI. This non-hematopoietic cell is clinically relevant. Gastrointestinal toxicity is common during and after abdominal and pelvic radiation therapy and limits the radiation dose in these regions. As observed with bone marrow, the administration of SCF to mice prior to TBI enhanced the survival of mouse duodenal crypt stem cells. The maximum enhancement of survival was seen when 100 μ/kg of SCF was given intraperitoneally 8 h before irradiation. This regimen increased the survival of duodenal crypt stem cells after 12.0 Gy TBI from 22.5 ± 0.7 per duodenal cross section for controls to 30.0 ± 1.7 after treatment with SCF (P=0.03). The TBI dose producing 50% mortality of 6 days (LD 50/6 ) was increased from 14.9 Gy for control mice to 19.0 Gy for mice treated with SCF (dose modification factor = 1.28). These findings demonstrate that SCF (dose modification factor = 1.28). These findings demonstrate that SCF has radioprotective effects on a non-hematopoietic stem cell population and suggest that SCF may be of clinical value in preventing radiation injury to the intestine. 29 refs., 4 figs

Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

NARCIS (Netherlands)

J.A. Pulikkan (John); D. Madera (Dmitri); L. Xue (Liting); P. Bradley (Paul); S.F. Landrette (Sean Francis); Y.-H. Kuo (Ya-Huei); S. Abbas (Saman); L.J. Zhu (Lihua Julie); P.J.M. Valk (Peter); L.H. Castilla (Lucio)

2012-01-01

textabstractOncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by

α-Syntrophin is involved in the survival signaling pathway in myoblasts under menadione-induced oxidative stress.

Science.gov (United States)

Lim, Jeong-A; Choi, Su Jin; Moon, Jae Yun; Kim, Hye Sun

2016-05-15

Dystrophin-deficient muscle is known to be more vulnerable to oxidative stress, but not much is known about the signaling pathway(s) responsible for this phenomenon. α-Syntrophin, a component of the dystrophin-glycoprotein complex, can function as a scaffold protein because of its multiple protein interaction domains. In this study, we investigated the role of α-syntrophin in C2 myoblasts under menadione-induced oxidative stress. We found that the protein level of α-syntrophin was elevated when cells were exposed to menadione. To investigate the function of α-syntrophin during oxidative stress, we established α-syntrophin-overexpressing and knockdown cell lines. The α-syntrophin-overexpressing cells were resistant to the menadione-induced oxidative stress. In addition, survival signalings such as protein kinase B (Akt) phosphorylation and the Bcl-2/BAX ratio were increased in these cells. On the other hand, apoptotic signals such as cleavage of caspase-3 and poly ADP ribose polymerase (PARP) were increased in the α-syntrophin knockdown cells. Furthermore, Ca(2+)influx, which is known to increase when cells are exposed to oxidative stress, decreased in the α-syntrophin-overexpressing cells, but increased in the knockdown cells. These results suggest that α-syntrophin plays a pivotal role in the survival pathway triggered by menadione-induced oxidative stress in cultured myoblasts. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

Science.gov (United States)

Fu, Di; Li, Yingchun; Li, Jia; Shi, Xiaoyan; Yang, Ronghui; Zhong, Yuan; Wang, Huihan; Liao, Aijun

2017-01-01

Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

Data-Driven Iterative Vibration Signal Enhancement Strategy Using Alpha Stable Distribution

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Grzegorz Żak

2017-01-01

Full Text Available The authors propose a novel procedure for enhancement of the signal to noise ratio in vibration data acquired from machines working in mining industry environment. Proposed method allows performing data-driven reduction of the deterministic, high energy, and low frequency components. Furthermore, it provides a way to enhance signal of interest. Procedure incorporates application of the time-frequency decomposition, α-stable distribution based signal modeling, and stability parameter in the time domain as a stoppage criterion for iterative part of the procedure. An advantage of the proposed algorithm is data-driven, automative detection of the informative frequency band as well as band with high energy due to the properties of the used distribution. Furthermore, there is no need to have knowledge regarding kinematics, speed, and so on. The proposed algorithm is applied towards real data acquired from the belt conveyor pulley drive’s gearbox.

Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells.

Science.gov (United States)

Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-Ichiro

2016-10-15

The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy. Cancer Res; 76(20); 6030-42. ©2016 AACR. ©2016 American Association for Cancer Research.

Stem cell death and survival in heart regeneration and repair.

Science.gov (United States)

Abdelwahid, Eltyeb; Kalvelyte, Audrone; Stulpinas, Aurimas; de Carvalho, Katherine Athayde Teixeira; Guarita-Souza, Luiz Cesar; Foldes, Gabor

2016-03-01

Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

The p75NTR mediates a bifurcated signal transduction cascade through the NFκB and JNK pathways to inhibit cell survival

International Nuclear Information System (INIS)

Allen, Jeffrey; Khwaja, Fatima; Byers, Stephen; Djakiew, Daniel

2005-01-01

p75 NTR is most abundantly expressed in the nervous system, but is also widely expressed in many other organs and tissues where it primarily functions as a negative regulator of cell survival. In the prostate, p75 NTR functions as an inhibitory protein capable of slowing proliferation and inducing apoptosis. It has been shown that p75 NTR is expressed in the normal prostate, progressively lost from malignant tumor cells in vivo, and largely absent from prostate cancer cell lines derived from metastases. Although the role of p75 NTR in prostate cancer has been well established, the signal transduction pathway that mediates its inhibitory activity has only been partially elucidated. This study demonstrates that exogenous expression of p75 NTR down-regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in reduced expression of potent transcription effectors. This two-arm signal transduction cascade was directly linked to the upstream receptor by using dominant-negative deletion constructs of p75 NTR that rescued tumor cells from p75 NTR -induced loss of survival and promotion of apoptosis. Furthermore, the dominant negatives rescued alterations in the levels of signal transduction intermediates. Conversely, the use of kinase-inactive intermediates that are downstream of the receptor further reduced expression of involved transcription effectors and reduced survival of the cells. These results provide a definitive link between the proximate p75 NTR and signal transduction intermediates leading to the transcription effectors NFκB and JNK, with associated growth suppression and induction of apoptosis

Survival of Probiotic Lactobacilli in Acidic Environments Is Enhanced in the Presence of Metabolizable Sugars

OpenAIRE

Corcoran, B. M.; Stanton, C.; Fitzgerald, G. F.; Ross, R. P.

2005-01-01

Lactobacillus rhamnosus GG is an industrially significant probiotic strain with proven health benefits. In this study, the effect of glucose on L. rhamnosus GG survival was analyzed in simulated gastric juice at pH 2.0. It was found that the presence of 19.4 mM glucose resulted in up to 6-log10-enhanced survival following 90 min of exposure. Further work with dilute HCl confirmed that glucose was the sole component responsible. Comparative analysis with other Lactobacillus strains revealed th...

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

Science.gov (United States)

Rosas-Ballina, Mauricio; Ferrer, Sergio Valdés; Dancho, Meghan; Ochani, Mahendar; Katz, David; Cheng, Kai Fan; Olofsson, Peder S.; Chavan, Sangeeta S.; Al-Abed, Yousef; Tracey, Kevin J.; Pavlov, Valentin A.

2014-01-01

Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases. PMID:25063706

Enhanced endogenous type I interferon cell-driven survival and inhibition of spontaneous apoptosis by Riluzole

International Nuclear Information System (INIS)

Achour, Ammar; M'Bika, Jean-Pierre; Biquard, Jean-Michel

2009-01-01

Highly active antiretroviral therapy (HAART), although effective in improving the survival of HIV-1-infected individuals, has not been able to reconstitute the adaptive immune response. We have described the use of novel chemical agents to restore T-cell survival/proliferation by inducing cytokine production. Due to its cationic amphiphilic structure, these molecules appear to enhance immune restoration. In this study, we investigated the action of Riluzole (2-amino-6-trifuromethoxybenzothiazole) in HIV-1 infection. Riluzole is able to increase (effective dose from 1 to 1000 nM) the cell-survival of T cells from HIV-1-infected patients and inhibit spontaneous apoptosis. The immunomodulatory effect of riluzole-sensitized cells was ascribed to endogenous type I interferon (IFN) derived from monocytes. Riluzole might be used for restoring the cell survival of immunocompromised patients and eliminating latent infected cells upon HIV-1 reactivation

Socially selected ornaments and fitness: Signals of fighting ability in paper wasps are positively associated with survival, reproductive success, and rank.

Science.gov (United States)

Tibbetts, Elizabeth A; Forrest, Taylor; Vernier, Cassondra; Jinn, Judy; Madagame, Andrew

2015-11-01

Many animals have ornaments that mediate choice and competition in social and sexual contexts. Individuals with elaborate sexual ornaments typically have higher fitness than those with less elaborate ornaments, but less is known about whether socially selected ornaments are associated with fitness. Here, we test the relationship between fitness and facial patterns that are a socially selected signal of fighting ability in Polistes dominula wasps. We found wasps that signal higher fighting ability have larger nests, are more likely to survive harsh winters, and obtain higher dominance rank than wasps that signal lower fighting ability. In comparison, body weight was not associated with fitness. Larger wasps were dominant over smaller wasps, but showed no difference in nest size or survival. Overall, the positive relationship between wasp facial patterns and fitness indicates that receivers can obtain diverse information about a signaler's phenotypic quality by paying attention to socially selected ornaments. Therefore, there are surprisingly strong parallels between the information conveyed by socially and sexually selected signals. Similar fitness relationships in social and sexually selected signals may be one reason it can be difficult to distinguish the role of social versus sexual selection in ornament evolution. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Can Survival Processing Enhance Story Memory? Testing the Generalizability of the Adaptive Memory Framework

Science.gov (United States)

Seamon, John G.; Bohn, Justin M.; Coddington, Inslee E.; Ebling, Maritza C.; Grund, Ethan M.; Haring, Catherine T.; Jang, Sue-Jung; Kim, Daniel; Liong, Christopher; Paley, Frances M.; Pang, Luke K.; Siddique, Ashik H.

2012-01-01

Research from the adaptive memory framework shows that thinking about words in terms of their survival value in an incidental learning task enhances their free recall relative to other semantic encoding strategies and intentional learning (Nairne, Pandeirada, & Thompson, 2008). We found similar results. When participants used incidental…

Effect of the size of silver nanoparticles on SERS signal enhancement

Science.gov (United States)

He, Rui Xiu; Liang, Robert; Peng, Peng; Norman Zhou, Y.

2017-08-01

The localized surface plasmon resonance arising from plasmonic materials is beneficial in solution-based and thin-film sensing applications, which increase the sensitivity of the analyte being tested. Silver nanoparticles from 35 to 65 nm in diameter were synthesized using a low-temperature method and deposited in a monolayer on a (3-aminopropyl)triethoxysilane (APTES)-functionalized glass slide. The effect of particle size on monolayer structure, optical behavior, and surface-enhanced Raman scattering (SERS) is studied. While increasing particle size decreases particle coverage, it also changes the localized surface plasmon resonance and thus the SERS activity of individual nanoparticles. Using a laser excitation wavelength of 633 nm, the stronger localized surface plasmon resonance coupling to this excitation wavelength at larger particle sizes trumps the loss in surface coverage, and greater SERS signals are observed. The SERS signal enhancement accounts for the higher SERS signal, which was verified using a finite element model of a silver nanoparticle dimer with various nanoparticle sizes and separation distances.

Caffeine-enhanced survival of radiation-sensitive, repair-deficient Chinese hamster cells

International Nuclear Information System (INIS)

Utsumi, H.; Elkind, M.M.

1983-01-01

A clone of V79 Chinese hamster cells (V79-AL162/S-10) with unique properties has been isolated after a challenge of parental cells (V79-AL162) with 1 mM ouabain. Compared with parental cells, or with other clones isolated after the ouabain challenge, these cells form smaller colonies, are more sensitive to both x rays and fission-spectrum neutrons, and respond atypically to a postirradiation treatment with caffeine. Their enhanced response to x rays results mainly from a large reduction in the shoulder of their survival curve, probably because in late S phase, the most resistant phase in the cell cycle, the survival curve of these cells has a reduced shoulder width. Caffeine, and to a lesser extent theophylline, added to the colony-forming medium immediately after exposure appreciably increases the width of the shoulder of these sensitive cells, whereas caffeine has the opposite effect on the response of normal V79 cells. Thus the unique response of the V79-AL162/S-10 cells to a radiation posttreatment with caffeine (increased survival) results from a net increase in their ability to repair damage that is otherwise lethal; caffeine treatment ordinarly prevents normal V79 cells from repairing damage that is only potentially lethal

Preheat-induced signal enhancement in the infrared stimulated luminescence of young and bleached sediment samples

International Nuclear Information System (INIS)

Richardson, C.A.

2000-01-01

Natural and laboratory bleached surface and young samples of potassium feldspar sand separates and polymineral silt had their infrared stimulated luminescence (IRSL) signal measured before and after preheating at 220 deg. C for 10 min or 160 deg. C for 16 h. For both preheats, the laboratory bleached sand samples underwent a signal enhancement which was stable with laboratory storage. The youngest samples also showed natural signal enhancement. The silt sample showed no recuperation of bleached signal on preheating, but some in the natural signal. A range of filtered bleaches was applied to one surface sand sample. Signal levels before and after preheating were reduced by filtering out the UV from the bleaching spectrum. The unfiltered bleach, however, most closely reproduced the behaviour of the natural sample

SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt

Energy Technology Data Exchange (ETDEWEB)

Tanti, Goutam Kumar, E-mail: goutamjnu@hotmail.com; Pandey, Shweta; Goswami, Shyamal K.

2015-08-07

SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ-1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocalization in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimerization. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth. - Highlights: • Reactive oxygen species (ROS) play potential role in cancer cell proliferation. • It enhances the association between DJ-1 and Akt mediated by SG2NA. • In cancer cells SG2NA stabilizes DJ-1 by inhibiting it from proteosomal degradation. • DJ-1 then activates Akt and cancer cells get their property of enhanced proliferation by sustained activation of Akt. • Further study on this field could lead to new target for cancer therapy.

SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt

International Nuclear Information System (INIS)

Tanti, Goutam Kumar; Pandey, Shweta; Goswami, Shyamal K.

2015-01-01

SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ-1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocalization in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimerization. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth. - Highlights: • Reactive oxygen species (ROS) play potential role in cancer cell proliferation. • It enhances the association between DJ-1 and Akt mediated by SG2NA. • In cancer cells SG2NA stabilizes DJ-1 by inhibiting it from proteosomal degradation. • DJ-1 then activates Akt and cancer cells get their property of enhanced proliferation by sustained activation of Akt. • Further study on this field could lead to new target for cancer therapy

Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum (ER) stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells.

Science.gov (United States)

Ding, Youming; Chen, Xiaoyan; Wang, Bin; Yu, Bin; Ge, Jianhui

2018-04-15

b-AP15, a potent and selective inhibitor of the ubiquitin-specific peptidase 14 (USP14), displays in vitro and in vivo antitumor abilities on some types of cancer cells. However, the mechanism underlying its action is not well elucidated. The purposes of the present study are to observe the potential impacts of b-AP15 on cell survival of hepatocellular carcinoma cells and to investigate whether and how this compound inhibits some survival-promoting signaling pathways. We found that b-AP15 significantly decreased cell viability and increased cell apoptosis in a dose-dependent manner in hepatocellular carcinoma cells, along with the perturbation of cell cycle and the decreased expressions of cell cycle-related proteins. We also demonstrated that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were enhanced by b-AP15 supplementation. The inhibition of ER stress/UPR only partly attenuated the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. In addition, b-AP15 treatment inhibited Wnt/β-catenin and Notch1 signaling pathways, and suppressed phosphorylation of STAT3, Akt, and Erk1/2, which were not restored by the inhibition of ER stress/UPR. Furthermore, the expression levels of signaling molecules in Notch1 were reduced by specific inhibitor of Wnt/β-catenin pathway. Notably, either Wnt or Notch1 signaling inhibitor mitigated phosphorylation of STAT3, Akt, and Erk1/2, and mimicked the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. These results clearly indicate that b-AP15 induced cytotoxic response to hepatocellular carcinoma cells by augmenting ER stress/UPR and inhibiting Wnt/Notch1 signaling pathways. This new finding provides a novel mechanism by which b-AP15 produces its antitumor therapeutic effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Prolonged hypoxia increases survival even in Zebrafish (Danio rerio showing cardiac arrhythmia.

Directory of Open Access Journals (Sweden)

Renate Kopp

Full Text Available Tolerance towards hypoxia is highly pronounced in zebrafish. In this study even beneficial effects of hypoxia, specifically enhanced survival of zebrafish larvae, could be demonstrated. This effect was actually more pronounced in breakdance mutants, which phenotypically show cardiac arrhythmia. Breakdance mutants (bre are characterized by chronically reduced cardiac output. Despite an about 50% heart rate reduction, they become adults, but survival rate significantly drops to 40%. Normoxic bre animals demonstrate increased hypoxia inducible factor 1 a (Hif-1α expression, which indicates an activated hypoxic signaling pathway. Consequently, cardiovascular acclimation, like cardiac hypertrophy and increased erythrocyte concentration, occurs. Thus, it was hypothesized, that under hypoxic conditions survival might be even more reduced. When bre mutants were exposed to hypoxic conditions, they surprisingly showed higher survival rates than under normoxic conditions and even reached wildtype values. In hypoxic wildtype zebrafish, survival yet exceeded normoxic control values. To specify physiological acclimation, cardiovascular and metabolic parameters were measured before hypoxia started (3 dpf, when the first differences in survival rate occurred (7 dpf and when survival rate plateaued (15 dpf. Hypoxic animals expectedly demonstrated Hif-1α accumulation and consequently enhanced convective oxygen carrying capacity. Moreover, bre animals showed a significantly enhanced heart rate under hypoxic conditions, which reached normoxic wildtype values. This improvement in convective oxygen transport ensured a sufficient oxygen and nutrient supply and was also reflected in the significantly higher mitochondrial activity. The highly optimized energy metabolism observed in hypoxic zebrafish larvae might be decisive for periods of higher energy demand due to organ development, growth and increased activity. However, hypoxia increased survival only during a

c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling.

Directory of Open Access Journals (Sweden)

Nanako Kawaguchi

2010-12-01

Full Text Available Resident c-kit positive (c-kitpos cardiac stem cells (CSCs could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.

Romidepsin targets multiple survival signaling pathways in malignant T cells

International Nuclear Information System (INIS)

Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

2015-01-01

Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

Polyandry promotes enhanced offspring survival in decorated crickets.

Science.gov (United States)

Ivy, Tracie M; Sakaluk, Scott K

2005-01-01

Although female multiple mating is ubiquitous in insects, its adaptive significance remains poorly understood. Benefits to multiple mating can accrue via direct material benefits, indirect genetic benefits, or both. We investigated the effects of multiple mating in the decorated cricket, Gryllodes sigillatus, by simultaneously varying the number of times that females mated and the number of different males with which they mated, measuring aspects of female fecundity and elements of offspring performance and viability. Multiple matings resulted in enhanced female fitness relative to single matings when females mated with different partners, but not when females mated repeatedly with the same male. Specifically, polyandrous females produced significantly more offspring surviving to reproductive maturity than did monogamous females mating once or mating repeatedly with the same male. These results suggest that the benefit females gain from multiple mating is influenced primarily by genetic and not material benefits.

Low dose gamma irradiation enhances defined signaling components of intercellular reactive oxygen-mediated apoptosis induction

International Nuclear Information System (INIS)

Bauer, G

2011-01-01

Transformed cells are selectively removed by intercellular ROS-mediated induction of apoptosis. Signaling is based on the HOCl and the NO/peroxynitrite pathway (major pathways) and the nitryl chloride and the metal-catalyzed Haber-Weiss pathway (minor pathways). During tumor progression, resistance against intercellular induction of apoptosis is acquired through expression of membrane-associated catalase. Low dose radiation of nontransformed cells has been shown to enhance intercellular induction of apoptosis. The present study was performed to define the signaling components which are modulated by low dose gamma irradiation. Low dose radiation induced the release of peroxidase from nontransformed, transformed and tumor cells. Extracellular superoxide anion generation was strongly enhanced in the case of transformed cells and tumor cells, but not in nontransformed cells. Enhancement of peroxidase release and superoxide anion generation either increased intercellular induction of apoptosis of transformed cells, or caused a partial protection under specific signaling conditions. In tumor cells, low dose radiation enhanced the production of major signaling components, but this had no effect on apoptosis induction, due to the strong resistance mechanism of tumor cells. Our data specify the nature of low dose radiation-induced effects on specific signaling components of intercellular induction of apoptosis at defined stages of multistep carcinogenesis.

Fusarium oxysporum volatiles enhance plant growth via affecting auxin transport and signaling

Directory of Open Access Journals (Sweden)

Vasileios eBitas

2015-11-01

Full Text Available Volatile organic compounds (VOCs have well-documented roles in plant-plant communication and directing animal behavior. In this study, we examine the less understood roles of VOCs in plant-fungal relationships. Phylogenetically and ecologically diverse strains of Fusarium oxysporum, a fungal species complex that often resides in the rhizosphere of assorted plants, produce volatile compounds that augment shoot and root growth of Arabidopsis thaliana and tobacco. Growth responses of A. thaliana hormone signaling mutants and expression patterns of a GUS reporter gene under the auxin-responsive DR5 promoter supported the involvement of auxin signaling in F. oxysporum volatile-mediated growth enhancement. In addition, 1-naphthylthalamic acid, an inhibitor of auxin efflux, negated F. oxysporum volatile-mediated growth enhancement in both plants. Comparison of the profiles of volatile compounds produced by F. oxysporum strains that differentially affected plant growth suggests that the relative compositions of both growth inhibitory and stimulatory compounds may determine the degree of plant growth enhancement. Volatile-mediated signaling between fungi and plants may represent a potentially conserved, yet mostly overlooked, mechanism underpinning plant-fungus interactions and fungal niche adaption.

Signal Enhancement as Minimization of Relevant Information Loss

OpenAIRE

Geiger, Bernhard C.; Kubin, Gernot

2012-01-01

We introduce the notion of relevant information loss for the purpose of casting the signal enhancement problem in information-theoretic terms. We show that many algorithms from machine learning can be reformulated using relevant information loss, which allows their application to the aforementioned problem. As a particular example we analyze principle component analysis for dimensionality reduction, discuss its optimality, and show that the relevant information loss can indeed vanish if the r...

Engineering signal peptides for enhanced protein secretion from Lactococcus lactis.

Science.gov (United States)

Ng, Daphne T W; Sarkar, Casim A

2013-01-01

Lactococcus lactis is an attractive vehicle for biotechnological production of proteins and clinical delivery of therapeutics. In many such applications using this host, it is desirable to maximize secretion of recombinant proteins into the extracellular space, which is typically achieved by using the native signal peptide from a major secreted lactococcal protein, Usp45. In order to further increase protein secretion from L. lactis, inherent limitations of the Usp45 signal peptide (Usp45sp) must be elucidated. Here, we performed extensive mutagenesis on Usp45sp to probe the effects of both the mRNA sequence (silent mutations) and the peptide sequence (amino acid substitutions) on secretion. We screened signal peptides based on their resulting secretion levels of Staphylococcus aureus nuclease and further evaluated them for secretion of Bacillus subtilis α-amylase. Silent mutations alone gave an increase of up to 16% in the secretion of α-amylase through a mechanism consistent with relaxed mRNA folding around the ribosome binding site and enhanced translation. Targeted amino acid mutagenesis in Usp45sp, combined with additional silent mutations from the best clone in the initial screen, yielded an increase of up to 51% in maximum secretion of α-amylase while maintaining secretion at lower induction levels. The best sequence from our screen preserves the tripartite structure of the native signal peptide but increases the positive charge of the n-region. Our study presents the first example of an engineered L. lactis signal peptide with a higher secretion yield than Usp45sp and, more generally, provides strategies for further enhancing protein secretion in bacterial hosts.

Enhancement of small signal stability of a DFIG-based wind power ...

African Journals Online (AJOL)

International Journal of Engineering, Science and Technology ... logic controllers for enhancing the small signal stability of DFIG-based wind integrated power system. ... state space model, eigenvalue analysis, fuzzy logic based tuning circuits ...

Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

Science.gov (United States)

Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

2017-10-01

The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion.

Science.gov (United States)

Kaur, Tejbeer; Zamani, Darius; Tong, Ling; Rubel, Edwin W; Ohlemiller, Kevin K; Hirose, Keiko; Warchol, Mark E

2015-11-11

Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells. We used a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX3CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea. It is known that damage to the inner ear leads to recruitment of inflammatory cells (macrophages), but the chemical signals that initiate this recruitment and the functions of macrophages in the damaged ear are unclear. Here we show that fractalkine signaling regulates macrophage recruitment into the cochlea and also promotes the survival of cochlear afferents after

Enhancement of Chiroptical Signals by Circular Differential Mie Scattering of Nanoparticles

OpenAIRE

SeokJae Yoo; Q-Han Park

2015-01-01

We enhance the weak optical signals of small chiral molecules via circular differential Mie scattering (CDMS) of nanoparticles immersed in them. CDMS is the preferential Mie scattering of left- and right-handed circularly polarized light by nanoparticles whose sizes are about the same as the wavelength of light. Solving the Mie scattering theory for chiral media, we find that the CDMS signal of the particle is linearly proportional to the chirality parameter κ of the molecules. This linear am...

p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD

DEFF Research Database (Denmark)

Harada, H; Andersen, Jens S.; Mann, M

2001-01-01

Cytokines often deliver simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) is known to regulate cell growth by inducing protein synthesis components. We purified membrane-based p70S6K as a kinase responsible for site-specific phospho...

Drak2 Does Not Regulate TGF-β Signaling in T Cells.

Directory of Open Access Journals (Sweden)

Tarsha L Harris

Full Text Available Drak2 is a serine/threonine kinase expressed highest in T cells and B cells. Drak2-/- mice are resistant to autoimmunity in mouse models of type 1 diabetes and multiple sclerosis. Resistance to these diseases occurs, in part, because Drak2 is required for the survival of autoreactive T cells that induce disease. However, the molecular mechanisms by which Drak2 affects T cell survival and autoimmunity are not known. A recent report demonstrated that Drak2 negatively regulated transforming growth factor-β (TGF-β signaling in tumor cell lines. Thus, increased TGF-β signaling in the absence of Drak2 may contribute to the resistance to autoimmunity in Drak2-/- mice. Therefore, we examined if Drak2 functioned as a negative regulator of TGF-β signaling in T cells, and whether the enhanced susceptibility to death of Drak2-/- T cells was due to augmented TGF-β signaling. Using several in vitro assays to test TGF-β signaling and T cell function, we found that activation of Smad2 and Smad3, which are downstream of the TGF-β receptor, was similar between wildtype and Drak2-/- T cells. Furthermore, TGF-β-mediated effects on naïve T cell proliferation, activated CD8+ T cell survival, and regulatory T cell induction was similar between wildtype and Drak2-/- T cells. Finally, the increased susceptibility to death in the absence of Drak2 was not due to enhanced TGF-β signaling. Together, these data suggest that Drak2 does not function as a negative regulator of TGF-β signaling in primary T cells stimulated in vitro. It is important to investigate and discern potential molecular mechanisms by which Drak2 functions in order to better understand the etiology of autoimmune diseases, as well as to validate the use of Drak2 as a target for therapeutic treatment of these diseases.

Enhanced malignant transformation is accompanied by increased survival recovery after ionizing radiation in Chinese hamster embryo fibroblasts

International Nuclear Information System (INIS)

Boothman, D.A.

1994-01-01

Transformed Chinese hamster embryo fibroblasts (CHEF), which gradually increase in tumor-forming ability in nude mice, were isolated from normal diploid CHEF/18 cells. Transformed CHEF cells (i.e., T30-4 > 21-2M3 > 21-2 > normal CHEF/18) showed gradual increases in potentially lethal damage (PLD) survival recovery. β-Lapachone and camptothecin, modulators of topoisomerase I (Topo I) activity, not only prevented survival recovery in normal as well as in tumor cells, but enhanced unscheduled DNA synthesis. These seemingly conflicting results are due to the fact that Topo I activity can be modulated by inhibitors to convert single-stranded DNA lesions into double-stranded breaks. Increases in unscheduled DNA synthesis may result from a continual supply of free ends, on which DNA repair processes may act. Altering Topo I activity with modulators appears to increase X-ray lethality via a DNA lesion modification suicide pathway. Cells down-regulate Topo I immediately after ionizing radiation to prevent Topo I-mediated lesion modification and to enhance survival recovery. 16 refs., 3 figs., 1 tab

Integration and enhancement of low-level signals from air-pollution monitoring sensors

Energy Technology Data Exchange (ETDEWEB)

Dowd, G F; Dubois, L; Monkman, J L

1975-09-01

In this paper, we have demonstrated how signal enhancement techniques would be advantageous in the low-level analysis of air pollutants. We have further shown what type of signal-to-noise gain may be expected from an off-the-shelf, inexpensive run-of-the-mill mercury monitor. As long as an evoked response time constant is introduced into the measuring system, noise of a random nature may be reduced to such an extent that trace signals, buried deep in the electrical background, may be reliably measured. If we couple this type of analysis to a multi-parameter mercury analyzer, contributing factors may be evaluated. This will result in a more efficient system application. We have also reported a manner in which evoked response time is related to instrument onset time. However, there are other methods for obtaining an evoked response. Of note is the use of wavelength in the enhancement of spectrophotometric signals. In additional work now being carried out in our laboratory, there are indications that it is possible to relate this type of processing to SO/sub 2/ analyzing systems using conductometry. (auth)

Cytotoxic Vibrio T3SS1 Rewires Host Gene Expression to Subvert Cell Death Signaling and Activate Cell Survival Networks

Science.gov (United States)

De Nisco, Nicole J.; Kanchwala, Mohammed; Li, Peng; Fernandez, Jessie; Xing, Chao; Orth, Kim

2017-01-01

Bacterial effectors are potent manipulators of host signaling pathways. The marine bacterium Vibrio parahaemolyticus (V. para), delivers effectors into host cells through two type three secretion systems (T3SS). The ubiquitous T3SS1 is vital for V. para survival in the environment, whereas T3SS2 causes acute gastroenteritis in human hosts. Although the natural host is undefined, T3SS1 effectors attack highly conserved cellular processes and pathways to orchestrate non-apoptotic cell death. Much is known about how T3SS1 effectors function in isolation, but we wanted to understand how their concerted action globally affects host cell signaling. To assess the host response to T3SS1, we compared gene expression changes over time in primary fibroblasts infected with V. para that have a functional T3SS1 (T3SS1+) to those in cells infected with V. para lacking T3SS1 (T3SS1−). Overall, the host transcriptional response to both T3SS1+ and T3SS1− V. para was rapid, robust, and temporally dynamic. T3SS1 re-wired host gene expression by specifically altering the expression of 398 genes. Although T3SS1 effectors target host cells at the posttranslational level to cause cytotoxicity, network analysis indicated that V. para T3SS1 also precipitates a host transcriptional response that initially activates cell survival and represses cell death networks. The increased expression of several key pro-survival transcripts mediated by T3SS1 was dependent on a host signaling pathway that is silenced later in infection by the posttranslational action of T3SS1. Taken together, our analysis reveals a complex interplay between roles of T3SS1 as both a transcriptional and posttranslational manipulator of host cell signaling. PMID:28512145

Pretreatment Evaluation of Microcirculation by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Survival in Primary Rectal Cancer Patients

Energy Technology Data Exchange (ETDEWEB)

DeVries, Alexander Friedrich [Department of Radio-Oncology, Academic Teaching Hospital Feldkirch, Feldkirch (Austria); Piringer, Gudrun, E-mail: gudrun.piringer@hotmail.com [Department of Oncology, Wels-Grieskirchen Medical Hospital, Wels (Austria); Kremser, Christian; Judmaier, Werner [Department of Radiology, Innsbruck Medical University, Innsbruck (Austria); Saely, Christoph Hubert [Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch (Austria); Lukas, Peter [Department of Radio-Oncology, Innsbruck Medical University, Innsbruck (Austria); Öfner, Dietmar [Department of Surgery, Paracelsus Medical University, Salzburg (Austria)

2014-12-01

Purpose: To investigate the prognostic value of the perfusion index (PI), a microcirculatory parameter estimated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which integrates information on both flow and permeability, to predict overall survival and disease-free survival in patients with primary rectal cancer. Methods and Materials: A total of 83 patients with stage cT3 rectal cancer requiring neoadjuvant chemoradiation were investigated with DCE-MRI before start of therapy. Contrast-enhanced dynamic T{sub 1} mapping was obtained, and a simple data analysis strategy based on the calculation of the maximum slope of the tissue concentration–time curve divided by the maximum of the arterial input function was used as a measure of tumor microcirculation (PI), which integrates information on both flow and permeability. Results: In 39 patients (47.0%), T downstaging (ypT0-2) was observed. During a mean (±SD) follow-up period of 71 ± 29 months, 58 patients (69.9%) survived, and disease-free survival was achieved in 45 patients (54.2%). The mean PI (PImean) averaged over the group of nonresponders was significantly higher than for responders. Additionally, higher PImean in age- and gender-adjusted analyses was strongly predictive of therapy nonresponse. Most importantly, PImean strongly and significantly predicted disease-free survival (unadjusted hazard ratio [HR], 1.85 [ 95% confidence interval, 1.35-2.54; P<.001)]; HR adjusted for age and sex, 1.81 [1.30-2.51]; P<.001) as well as overall survival (unadjusted HR 1.42 [1.02-1.99], P=.040; HR adjusted for age and sex, 1.43 [1.03-1.98]; P=.034). Conclusions: This analysis identifies PImean as a novel biomarker that is predictive for therapy response, disease-free survival, and overall survival in patients with primary locally advanced rectal cancer.

Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.

Science.gov (United States)

Kim, Byung Hak; Min, Yun Sook; Choi, Jung Sook; Baeg, Gyeong Hun; Kim, Young Soo; Shin, Jong Wook; Kim, Tae Yoon; Ye, Sang Kyu

2011-05-31

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.

EELS signal enhancement by means of beam precession in the TEM

International Nuclear Information System (INIS)

Estradé, Sonia; Portillo, Joaquim; Yedra, Lluís; Rebled, José Manuel; Peiró, Francesca

2012-01-01

EELS is nowadays a most relevant characterization tool as it provides chemical and electronic information with an extraordinary spatial resolution. When a crystal is viewed in zone axis in the TEM, there is channelling of the electrons along the atom columns, which strongly reduce the EELS signal, so that it is generally advised to work slightly off the zone axis to collect EELS data, which may not always be possible or advantageous. In the present work, we demonstrate the use of precession to compensate for the reduction of EELS signal when in the zone axis. -- Highlights: ► Channelling compromises EELS signal in zone axis. ► Precession can be used to get rid of channelling effects. ► Use of precession to enhance EELS signal in the zone axis is demonstrated.

Exogenous Modulation of Retinoic Acid Signaling Affects Adult RGC Survival in the Frog Visual System after Optic Nerve Injury.

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Mildred V Duprey-Díaz

Full Text Available After lesions to the mammalian optic nerve, the great majority of retinal ganglion cells (RGCs die before their axons have even had a chance to regenerate. Frog RGCs, on the other hand, suffer only an approximately 50% cell loss, and we have previously investigated the mechanisms by which the application of growth factors can increase their survival rate. Retinoic acid (RA is a vitamin A-derived lipophilic molecule that plays major roles during development of the nervous system. The RA signaling pathway is also present in parts of the adult nervous system, and components of it are upregulated after injury in peripheral nerves but not in the CNS. Here we investigate whether RA signaling affects long-term RGC survival at 6 weeks after axotomy. Intraocular injection of all-trans retinoic acid (ATRA, the retinoic acid receptor (RAR type-α agonist AM80, the RARβ agonist CD2314, or the RARγ agonist CD1530, returned axotomized RGC numbers to almost normal levels. On the other hand, inhibition of RA synthesis with disulfiram, or of RAR receptors with the pan-RAR antagonist Ro-41-5253, or the RARβ antagonist LE135E, greatly reduced the survival of the axotomized neurons. Axotomy elicited a strong activation of the MAPK, STAT3 and AKT pathways; this activation was prevented by disulfiram or by RAR antagonists. Finally, addition of exogenous ATRA stimulated the activation of the first two of these pathways. Future experiments will investigate whether these strong survival-promoting effects of RA are mediated via the upregulation of neurotrophins.

Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

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Kim, Kyungsoo; Lim, Sung-Ho; Lee, Jaeseok; Kang, Won-Seok; Moon, Cheil; Choi, Ji-Woong

2016-01-01

Electroencephalograms (EEGs) measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI) studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR) is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP) signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE) schemes based on a joint maximum likelihood (ML) criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°. PMID:27322267

Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

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Kyungsoo Kim

2016-06-01

Full Text Available Electroencephalograms (EEGs measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE schemes based on a joint maximum likelihood (ML criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°.

Security Enhancement of Wireless Sensor Networks Using Signal Intervals.

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Moon, Jaegeun; Jung, Im Y; Yoo, Jaesoo

2017-04-02

Various wireless technologies, such as RF, Bluetooth, and Zigbee, have been applied to sensor communications. However, the applications of Bluetooth-based wireless sensor networks (WSN) have a security issue. In one pairing process during Bluetooth communication, which is known as simple secure pairing (SSP), the devices are required to specify I/O capability or user interference to prevent man-in-the-middle (MITM) attacks. This study proposes an enhanced SSP in which a nonce to be transferred is converted to a corresponding signal interval. The quantization level, which is used to interpret physical signal intervals, is renewed at every connection by the transferred nonce and applied to the next nonce exchange so that the same signal intervals can represent different numbers. Even if attackers eavesdrop on the signals, they cannot understand what is being transferred because they cannot determine the quantization level. Furthermore, the proposed model does not require exchanging passkeys as data, and the devices are secure in the case of using a fixed PIN. Subsequently, the new quantization level is calculated automatically whenever the same devices attempt to connect with each other. Therefore, the pairing process can be protected from MITM attacks and be convenient for users.

Identification of a Novel TGFβ/PKA Signaling Transduceome in Mediating Control of Cell Survival and Metastasis in Colon Cancer

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Rajput, Ashwani; Teggart, Carol A.; Brattain, Lisa E.; Weber, Hannah R.; Chowdhury, Aparajita; Brattain, Michael G.

2011-01-01

Background Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown. Methodology/Principal Findings Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival. Conclusion/Significance This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors. PMID:21559296

Identification of a novel TGFβ/PKA signaling transduceome in mediating control of cell survival and metastasis in colon cancer.

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Sanjib Chowdhury

2011-05-01

Full Text Available Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown.Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival.This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.

Inhibition of human lung cancer cell proliferation and survival by wine

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2014-01-01

Background Compounds of plant origin and food components have attracted scientific attention for use as agents for cancer prevention and treatment. Wine contains polyphenols that were shown to have anti-cancer and other health benefits. The survival pathways of Akt and extracellular signal-regulated kinase (Erk), and the tumor suppressor p53 are key modulators of cancer cell growth and survival. In this study, we examined the effects of wine on proliferation and survival of human Non-small cell lung cancer (NSCLC) cells and its effects on signaling events. Methods Human NSCLC adenocarcinoma A549 and H1299 cells were used. Cell proliferation was assessed by thymidine incorporation. Clonogenic assays were used to assess cell survival. Immunoblotting was used to examine total and phosphorylated levels of Akt, Erk and p53. Results In A549 cells red wine inhibited cell proliferation and reduced clonogenic survival at doses as low as 0.02%. Red wine significantly reduced basal and EGF-stimulated Akt and Erk phosphorylation while it increased the levels of total and phosphorylated p53 (Ser15). Control experiments indicated that the anti-proliferative effects of wine were not mediated by the associated contents of ethanol or the polyphenol resveratrol and were independent of glucose transport into cancer cells. White wine also inhibited clonogenic survival, albeit at a higher doses (0.5-2%), and reduced Akt phosphorylation. The effects of both red and white wine on Akt phosphorylation were also verified in H1299 cells. Conclusions Red wine inhibits proliferation of lung cancer cells and blocks clonogenic survival at low concentrations. This is associated with inhibition of basal and EGF-stimulated Akt and Erk signals and enhancement of total and phosphorylated levels of p53. White wine mediates similar effects albeit at higher concentrations. Our data suggest that wine may have considerable anti-tumour and chemoprevention properties in lung cancer and deserves further

Neonatal maternal separation up-regulates protein signalling for cell survival in rat hypothalamus.

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Irles, Claudine; Nava-Kopp, Alicia T; Morán, Julio; Zhang, Limei

2014-05-01

We have previously reported that in response to early life stress, such as maternal hyperthyroidism and maternal separation (MS), the rat hypothalamic vasopressinergic system becomes up-regulated, showing enlarged nuclear volume and cell number, with stress hyperresponsivity and high anxiety during adulthood. The detailed signaling pathways involving cell death/survival, modified by adverse experiences in this developmental window remains unknown. Here, we report the effects of MS on cellular density and time-dependent fluctuations of the expression of pro- and anti-apoptotic factors during the development of the hypothalamus. Neonatal male rats were exposed to 3 h-daily MS from postnatal days 2 to 15 (PND 2-15). Cellular density was assessed in the hypothalamus at PND 21 using methylene blue staining, and neuronal nuclear specific protein and glial fibrillary acidic protein immunostaining at PND 36. Expression of factors related to apoptosis and cell survival in the hypothalamus was examined at PND 1, 3, 6, 9, 12, 15, 20 and 43 by Western blot. Rats subjected to MS exhibited greater cell-density and increased neuronal density in all hypothalamic regions assessed. The time course of protein expression in the postnatal brain showed: (1) decreased expression of active caspase 3; (2) increased Bcl-2/Bax ratio; (3) increased activation of ERK1/2, Akt and inactivation of Bad; PND 15 and PND 20 were the most prominent time-points. These data indicate that MS can induce hypothalamic structural reorganization by promoting survival, suppressing cell death pathways, increasing cellular density which may alter the contribution of these modified regions to homeostasis.

Nerve Growth Factor in Cancer Cell Death and Survival

International Nuclear Information System (INIS)

Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M.

2011-01-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75 NTR , a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75 NTR . For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75 NTR . This latter signaling through p75 NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75 NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer

Optimal Noise Enhanced Signal Detection in a Unified Framework

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Ting Yang

2016-06-01

Full Text Available In this paper, a new framework for variable detectors is formulated in order to solve different noise enhanced signal detection optimal problems, where six different disjoint sets of detector and discrete vector pairs are defined according to the two inequality-constraints on detection and false-alarm probabilities. Then theorems and algorithms constructed based on the new framework are presented to search the optimal noise enhanced solutions to maximize the relative improvements of the detection and the false-alarm probabilities, respectively. Further, the optimal noise enhanced solution of the maximum overall improvement is obtained based on the new framework and the relationship among the three maximums is presented. In addition, the sufficient conditions for improvability or non-improvability under the two certain constraints are given. Finally, numerous examples are presented to illustrate the theoretical results and the proofs of the main theorems are given in the Appendix.

78 FR 76639 - Endangered and Threatened Wildlife and Plants; Enhancement of Survival Permit Application; Draft...

Science.gov (United States)

2013-12-18

...-FRES48010660150] Endangered and Threatened Wildlife and Plants; Enhancement of Survival Permit Application; Draft... Texas. The intent of the CCAA is to provide the oil and gas industry with the opportunity to voluntarily..., 9014 East 21 St., Tulsa, OK 74129, (918) 382-4501; (d) Austin, Texas ESFO, 10711 Burnet Rd., Suite 200...

Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: Comparison of three methods

International Nuclear Information System (INIS)

Onoda, Minori; Hyodo, Tomoko; Murakami, Takamichi; Okada, Masahiro; Uto, Tatsuro; Hori, Masatoshi; Miyati, Tosiaki

2015-01-01

Highlights: •Signal intensity is often used to evaluate hepatic enhancement with Gd-EOB-DTPA in the hepatobiliary phase. •Comparison of uncorrected signal intensity with T 1 value revealed signal intensity instability. •Measurement of uncorrected liver SI or SNR often yields erroneous results on late-phase gadoxetate MRI due to shimming and other optimization techniques. •Signal intensity corrected by scale and rescale slope from DICOM data gave comparable results. -- Abstract: Objective: To compare signal intensity (SI) correction using scale and rescale slopes with SI correction using SIs of spleen and muscle for quantifying multiphase hepatic contrast enhancement with Gd-EOB-DTPA by assessing their correlation with T 1 values generated from Look-Locker turbo-field-echo (LL-TFE) sequence data (ER-T 1 ). Materials and methods: Thirty patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in this prospective clinical study. For each patient, breath-hold T 1 -weighted fat-suppressed three-dimensional (3D) gradient echo sequences (e-THRIVE) were acquired before and 2 (first phase), 10 (second phase), and 20 min (third phase) after intravenous Gd-EOB-DTPA. Look-Locker turbo-field-echo (LL-TFE) sequences were acquired before and 1.5 (first phase), 8 (second phase), and 18 min (third phase) postcontrast. The liver parenchyma enhancement ratios (ER) of each phase were calculated using the SI from e-THRIVE sequences (ER-SI) and the T 1 values generated from LL-TFE sequence data (ER-T 1 ) respectively. ER-SIs were calculated in three ways: (1) comparing with splenic SI (ER-SI-s), (2) comparing with muscle SI (ER-SI-m), (3) using scale and rescale slopes obtained from DICOM headers (ER-SI-c), to eliminate the effects of receiver gain and scaling. For each of the first, second and third phases, correlation and agreement were assessed between each ER-SI and ER-T 1 . Results: In the first phase, all ER-SIs correlated weakly with ER-T 1 . In the second

Locally Applied Valproate Enhances Survival in Rats after Neocortical Treatment with Tetanus Toxin and Cobalt Chloride

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Dirk-Matthias Altenmüller

2013-01-01

Full Text Available Purpose. In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT plus cobalt chloride (CoCl2. Methods. In rats, VPA ( or sodium chloride (NaCl ( containing polycaprolactone (PCL implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. Results. All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (. In both groups, witnessed deaths occurred in the context of seizures. At least of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. Conclusions. The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.

Regulation of radial glial survival by signals from the meninges.

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Radakovits, Randor; Barros, Claudia S; Belvindrah, Richard; Patton, Bruce; Müller, Ulrich

2009-06-17

Radial glial cells (RGCs) in the developing cerebral cortex are progenitors for neurons and glia, and their processes serve as guideposts for migrating neurons. So far, it has remained unclear whether RGC processes also control the function of RGCs more directly. Here, we show that RGC numbers and cortical size are reduced in mice lacking beta1 integrins in RGCs. TUNEL stainings and time-lapse video recordings demonstrate that beta1-deficient RGCs processes detach from the meningeal basement membrane (BM) followed by apoptotic death of RGCs. Apoptosis is also induced by surgical removal of the meninges. Finally, mice lacking the BM components laminin alpha2 and alpha4 show defects in the attachment of RGC processes at the meninges, a reduction in cortical size, and enhanced apoptosis of RGC cells. Our findings demonstrate that attachment of RGC processes at the meninges is important for RGC survival and the control of cortical size.

Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

Science.gov (United States)

Kakar, Sanjeev; Einhorn, Thomas A; Vora, Siddharth; Miara, Lincoln J; Hon, Gregory; Wigner, Nathan A; Toben, Daniel; Jacobsen, Kimberly A; Al-Sebaei, Maisa O; Song, Michael; Trackman, Philip C; Morgan, Elise F; Gerstenfeld, Louis C; Barnes, George L

2007-12-01

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to

An Enhanced Empirical Wavelet Transform for Features Extraction from Wind Turbine Condition Monitoring Signals

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Pu Shi

2017-07-01

Full Text Available Feature extraction from nonlinear and non-stationary (NNS wind turbine (WT condition monitoring (CM signals is challenging. Previously, much effort has been spent to develop advanced signal processing techniques for dealing with CM signals of this kind. The Empirical Wavelet Transform (EWT is one of the achievements attributed to these efforts. The EWT takes advantage of Empirical Mode Decomposition (EMD in dealing with NNS signals but is superior to the EMD in mode decomposition and robustness against noise. However, the conventional EWT meets difficulty in properly segmenting the frequency spectrum of the signal, especially when lacking pre-knowledge of the signal. The inappropriate segmentation of the signal spectrum will inevitably lower the accuracy of the EWT result and thus raise the difficulty of WT CM. To address this issue, an enhanced EWT is proposed in this paper by developing a feasible and efficient spectrum segmentation method. The effectiveness of the proposed method has been verified by using the bearing and gearbox CM data that are open to the public for the purpose of research. The experiment has shown that, after adopting the proposed method, it becomes much easier and more reliable to segment the frequency spectrum of the signal. Moreover, benefitting from the correct segmentation of the signal spectrum, the fault-related features of the CM signals are presented more explicitly in the time-frequency map of the enhanced EWT, despite the considerable noise contained in the signal and the shortage of pre-knowledge about the machine being investigated.

Cross-modal enhancement of speech detection in young and older adults: does signal content matter?

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Tye-Murray, Nancy; Spehar, Brent; Myerson, Joel; Sommers, Mitchell S; Hale, Sandra

2011-01-01

The purpose of the present study was to examine the effects of age and visual content on cross-modal enhancement of auditory speech detection. Visual content consisted of three clearly distinct types of visual information: an unaltered video clip of a talker's face, a low-contrast version of the same clip, and a mouth-like Lissajous figure. It was hypothesized that both young and older adults would exhibit reduced enhancement as visual content diverged from the original clip of the talker's face, but that the decrease would be greater for older participants. Nineteen young adults and 19 older adults were asked to detect a single spoken syllable (/ba/) in speech-shaped noise, and the level of the signal was adaptively varied to establish the signal-to-noise ratio (SNR) at threshold. There was an auditory-only baseline condition and three audiovisual conditions in which the syllable was accompanied by one of the three visual signals (the unaltered clip of the talker's face, the low-contrast version of that clip, or the Lissajous figure). For each audiovisual condition, the SNR at threshold was compared with the SNR at threshold for the auditory-only condition to measure the amount of cross-modal enhancement. Young adults exhibited significant cross-modal enhancement with all three types of visual stimuli, with the greatest amount of enhancement observed for the unaltered clip of the talker's face. Older adults, in contrast, exhibited significant cross-modal enhancement only with the unaltered face. Results of this study suggest that visual signal content affects cross-modal enhancement of speech detection in both young and older adults. They also support a hypothesized age-related deficit in processing low-contrast visual speech stimuli, even in older adults with normal contrast sensitivity.

Visible light communications using predistortion signal to enhance the response of passive optical receiver

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Liu, Yang; Chen, Hung-Yu; Liang, Kevin; Wei, Liang-Yu; Chow, Chi-Wai; Yeh, Chien-Hung

2016-01-01

Traditional visible light communication (VLC) uses positive-intrinsic-negative photodiode (PD) or avalanche PD as the optical receivers (Rx). We demonstrate using a solar cell as the VLC Rx. The solar cell is flexible and low cost and converts the optical signal into an electrical signal directly without the need of external power supply. In addition to acting as the VLC passive Rx, the converted electrical signal from the solar cell can charge up the battery of the Rx nodes. Hence, the proposed scheme can be a promising candidate for the future Internet of Things network. However, a solar cell acting as a VLC Rx is very challenging, since the response of the solar cell is limited. Here, we propose and demonstrate using predistortion to significantly enhance the solar cell Rx response for the first time up to the authors' knowledge. Experimental results show that the response of the solar cell Rx is significantly enhanced; and the original 2-kHz detection bandwidth of the solar cell can be enhanced by 250 times for receiving 500-kbit/s VLC signal at a transmission distance of 1 m. The operation principle, the generated voltage by the solar cell, and the maximum data rates achieved at different transmission distances are also studied.

Microencapsulation of alginate-immobilized bagasse with Lactobacillus rhamnosus NRRL 442: enhancement of survivability and thermotolerance.

Science.gov (United States)

Shaharuddin, Shahrulzaman; Muhamad, Ida Idayu

2015-03-30

The aim of this research was to enhance the survivability of Lactobacillus rhamnosus NRRL 442 against heat exposure via a combination of immobilization and microencapsulation processes using sugarcane bagasse (SB) and sodium alginate (NaA), respectively. The microcapsules were synthesized using different alginate concentration of 1, 2 and 3% and NaA:SB ratio of 1:0, 1:1 and 1:1.5. This beneficial step of probiotic immobilization before microencapsulation significantly enhanced microencapsulation efficiency and cell survivability after heat exposure of 90°C for 30s. Interestingly, the microcapsule of SB-immobilized probiotic could obtain protection from heat using microencapsulation of NaA concentration as low as 1%. SEM images illustrated the incorporation of immobilized L. rhamnosus within alginate matrices and its changes after heat exposure. FTIR spectra confirmed the change in functional bonding in the presence of sugarcane bagasse, probiotic and alginate. The results demonstrated a great potential in the synthesis of heat resistant microcapsules for probiotic. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nerve Growth Factor in Cancer Cell Death and Survival

Energy Technology Data Exchange (ETDEWEB)

Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M., E-mail: adrienne.gorman@nuigalway.ie [Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway (Ireland)

2011-02-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75{sup NTR}, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75{sup NTR}. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75{sup NTR}. This latter signaling through p75{sup NTR} promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75{sup NTR} mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.

Security Enhancement of Wireless Sensor Networks Using Signal Intervals

Directory of Open Access Journals (Sweden)

Jaegeun Moon

2017-04-01

Full Text Available Various wireless technologies, such as RF, Bluetooth, and Zigbee, have been applied to sensor communications. However, the applications of Bluetooth-based wireless sensor networks (WSN have a security issue. In one pairing process during Bluetooth communication, which is known as simple secure pairing (SSP, the devices are required to specify I/O capability or user interference to prevent man-in-the-middle (MITM attacks. This study proposes an enhanced SSP in which a nonce to be transferred is converted to a corresponding signal interval. The quantization level, which is used to interpret physical signal intervals, is renewed at every connection by the transferred nonce and applied to the next nonce exchange so that the same signal intervals can represent different numbers. Even if attackers eavesdrop on the signals, they cannot understand what is being transferred because they cannot determine the quantization level. Furthermore, the proposed model does not require exchanging passkeys as data, and the devices are secure in the case of using a fixed PIN. Subsequently, the new quantization level is calculated automatically whenever the same devices attempt to connect with each other. Therefore, the pairing process can be protected from MITM attacks and be convenient for users.

Electrochemical immunoassay for thyroxine detection using cascade catalysis as signal amplified enhancer and multi-functionalized magnetic graphene sphere as signal tag

Energy Technology Data Exchange (ETDEWEB)

Han, Jing; Zhuo, Ying, E-mail: yingzhuo@swu.edu.cn; Chai, Yaqin; Yu, Yanqing; Liao, Ni; Yuan, Ruo, E-mail: yuanruo@swu.edu.cn

2013-08-06

Graphical abstract: -- Highlights: •A reusable electrochemical immunosensor is developed for thyroxine detection. •Cascade catalysis as signal amplified enhancer. •Multi-functionalized magnetic graphene sphere as signal tag. •The novel strategy has the advantages of high sensitivity, good selectivity and reproducibility. -- Abstract: This paper constructed a reusable electrochemical immunosensor for the detection of thyroxine at an ultralow concentration using cascade catalysis of cytochrome c (Cyt c) and glucose oxidase (GOx) as signal amplified enhancer. It is worth pointing out that numerous Cyt c and GOx were firstly carried onto the double-stranded DNA polymers based on hybridization chain reaction (HCR), and then the amplified responses could be achieved by cascade catalysis of Cyt c and GOx recycling with the help of glucose. Moreover, multi-functionalized magnetic graphene sphere was synthesized and used as signal tag, which not only exhibited good mechanical properties, large surface area and an excellent electron transfer rate of graphene, but also possessed excellent redox activity and desirable magnetic property. With a sandwich-type immunoreaction, the proposed cascade catalysis amplification strategy could greatly enhance the sensitivity for the detection of thyroxine. Under the optimal conditions, the immunosensor showed a wide linear ranged from 0.05 pg mL{sup −1} to 5 ng mL{sup −1} and a low detection limit down to 15 fg mL{sup −1}. Importantly, the proposed method offers promise for reproducible and cost-effective analysis of biological samples.

EASEPort NPWT System to Enhance Skin Graft Survival--A Simple Assembly.

Science.gov (United States)

Prasetyono, Theddeus O H; Rini, Irena Sakura; Wibisono, Cindy

2015-03-01

Skin graft has been known to be prone to failure. This study was aimed to make a simplification of the negative pressure wound therapy (NPWT), which follows EASEPort (effective, affordable, safe, easily handled, and portable) concept to support the take of skin graft. The design of the EASEPort-NPWT was then made and technically verified. Thereafter, an animal experimental study comparing the EASEPort-NPWT to the classic tie-over technique on skin graft over exudative wound was conducted. The EASEPort-NPWT was verified to be able to yield and sustain the subatmospheric pressure needed. In the animal study, the treatment group showed better skin graft survival rate (97.55 ± 11.18% take) than the control group (54.88 ± 19.73%) on day-7. Histopathology examination showed good quality of the skin structures taken from the treatment group, which was better than the structures of the skin in the control group. In summary, this study has been able to fulfill its objective to create a device following EASEPort concept. Subsequently, the EASEPort-NPWT was able to enhance skin graft survival rate in exudative wound.

Early survival factor deprivation in the olfactory epithelium enhances activity-dependent survival

Directory of Open Access Journals (Sweden)

Adrien eFrançois

2013-12-01

Full Text Available The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs. However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226. We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population towards detection of environmental odorants.

Low noise signal-to-noise ratio enhancing readout circuit for current-mediated active pixel sensors

International Nuclear Information System (INIS)

Ottaviani, Tony; Karim, Karim S.; Nathan, Arokia; Rowlands, John A.

2006-01-01

Diagnostic digital fluoroscopic applications continuously expose patients to low doses of x-ray radiation, posing a challenge to both the digital imaging pixel and readout electronics when amplifying small signal x-ray inputs. Traditional switch-based amorphous silicon imaging solutions, for instance, have produced poor signal-to-noise ratios (SNRs) at low exposure levels owing to noise sources from the pixel readout circuitry. Current-mediated amorphous silicon pixels are an improvement over conventional pixel amplifiers with an enhanced SNR across the same low-exposure range, but whose output also becomes nonlinear with increasing dosage. A low-noise SNR enhancing readout circuit has been developed that enhances the charge gain of the current-mediated active pixel sensor (C-APS). The solution takes advantage of the current-mediated approach, primarily integrating the signal input at the desired frequency necessary for large-area imaging, while adding minimal noise to the signal readout. Experimental data indicates that the readout circuit can detect pixel outputs over a large bandwidth suitable for real-time digital diagnostic x-ray fluoroscopy. Results from hardware testing indicate that the minimum achievable C-APS output current that can be discerned at the digital fluoroscopic output from the enhanced SNR readout circuit is 0.341 nA. The results serve to highlight the applicability of amorphous silicon current-mediated pixel amplifiers for large-area flat panel x-ray imagers

Biofilm formation enhances Helicobacter pylori survivability in vegetables.

Science.gov (United States)

Ng, Chow Goon; Loke, Mun Fai; Goh, Khean Lee; Vadivelu, Jamuna; Ho, Bow

2017-04-01

To date, the exact route and mode of transmission of Helicobacter pylori remains elusive. The detection of H. pylori in food using molecular approaches has led us to postulate that the gastric pathogen may survive in the extragastric environment for an extended period. In this study, we show that H. pylori prolongs its survival by forming biofilm and micro-colonies on vegetables. The biofilm forming capability of H. pylori is both strain and vegetable dependent. H. pylori strains were classified into high and low biofilm formers based on their highest relative biofilm units (BU). High biofilm formers survived longer on vegetables compared to low biofilm formers. The bacteria survived better on cabbage compared to other vegetables tested. In addition, images captured on scanning electron and confocal laser scanning microscopes revealed that the bacteria were able to form biofilm and reside as micro-colonies on vegetable surfaces, strengthening the notion of possible survival of H. pylori on vegetables for an extended period of time. Taken together, the ability of H. pylori to form biofilm on vegetables (a common food source for human) potentially plays an important role in its survival, serving as a mode of transmission of H. pylori in the extragastric environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Thrombopoietin/MPL signaling confers growth and survival capacity to CD41-positive cells in a mouse model of Evi1 leukemia.

Science.gov (United States)

Nishikawa, Satoshi; Arai, Shunya; Masamoto, Yosuke; Kagoya, Yuki; Toya, Takashi; Watanabe-Okochi, Naoko; Kurokawa, Mineo

2014-12-04

Ecotropic viral integration site 1 (Evi1) is a transcription factor that is highly expressed in hematopoietic stem cells and is crucial for their self-renewal capacity. Aberrant expression of Evi1 is observed in 5% to 10% of de novo acute myeloid leukemia (AML) patients and predicts poor prognosis, reflecting multiple leukemogenic properties of Evi1. Here, we show that thrombopoietin (THPO) signaling is implicated in growth and survival of Evi1-expressing cells using a mouse model of Evi1 leukemia. We first identified that the expression of megakaryocytic surface molecules such as ITGA2B (CD41) and the THPO receptor, MPL, positively correlates with EVI1 expression in AML patients. In agreement with this finding, a subpopulation of bone marrow and spleen cells derived from Evi1 leukemia mice expressed both CD41 and Mpl. CD41(+) Evi1 leukemia cells induced secondary leukemia more efficiently than CD41(-) cells in a serial bone marrow transplantation assay. Importantly, the CD41(+) cells predominantly expressing Mpl effectively proliferated and survived on OP9 stromal cells in the presence of THPO via upregulating BCL-xL expression, suggesting an essential role of the THPO/MPL/BCL-xL cascade in enhancing the progression of Evi1 leukemia. These observations provide a novel aspect of the diverse functions of Evi1 in leukemogenesis. © 2014 by The American Society of Hematology.

The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency.

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Workman, Aspen; Zhu, Liqian; Keel, Brittney N; Smith, Timothy P L; Jones, Clinton

2018-04-01

Sensory neurons in trigeminal ganglia (TG) of calves latently infected with bovine herpesvirus 1 (BoHV-1) abundantly express latency-related (LR) gene products, including a protein (ORF2) and two micro-RNAs. Recent studies in mouse neuroblastoma cells (Neuro-2A) demonstrated ORF2 interacts with β-catenin and a β-catenin coactivator, high-mobility group AT-hook 1 (HMGA1) protein, which correlates with increased β-catenin-dependent transcription and cell survival. β-Catenin and HMGA1 are readily detected in a subset of latently infected TG neurons but not TG neurons from uninfected calves or reactivation from latency. Consequently, we hypothesized that the Wnt/β-catenin signaling pathway is differentially expressed during the latency and reactivation cycle and an active Wnt pathway promotes latency. RNA-sequencing studies revealed that 102 genes associated with the Wnt/β-catenin signaling pathway were differentially expressed in TG during the latency-reactivation cycle in calves. Wnt agonists were generally expressed at higher levels during latency, but these levels decreased during dexamethasone-induced reactivation. The Wnt agonist bone morphogenetic protein receptor 2 (BMPR2) was intriguing because it encodes a serine/threonine receptor kinase that promotes neuronal differentiation and inhibits cell death. Another differentially expressed gene encodes a protein kinase (Akt3), which is significant because Akt activity enhances cell survival and is linked to herpes simplex virus 1 latency and neuronal survival. Additional studies demonstrated ORF2 increased Akt3 steady-state protein levels and interacted with Akt3 in transfected Neuro-2A cells, which correlated with Akt3 activation. Conversely, expression of Wnt antagonists increased during reactivation from latency. Collectively, these studies suggest Wnt signaling cooperates with LR gene products, in particular ORF2, to promote latency. IMPORTANCE Lifelong BoHV-1 latency primarily occurs in sensory neurons

New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

International Nuclear Information System (INIS)

Cojocari, Dan; Vellanki, Ravi N.; Sit, Brandon; Uehling, David; Koritzinsky, Marianne; Wouters, Bradly G.

2013-01-01

Background and purpose: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling arms. Here we explore the potential of targeting two of these arms with new potent small-molecule inhibitors designed against IRE1α and PERK. Methods: We utilized shRNAs and small-molecule inhibitors of IRE1α (4μ8c) and PERK (GSK-compound 39). XBP1 splicing and DNAJB9 mRNA was measured by qPCR and was used to monitor IRE1α activity. PERK activity was monitored by immunoblotting eIF2α phosphorylation and qPCR of DDIT3 mRNA. Hypoxia tolerance was measured using proliferation and clonogenic cell survival assays of cells exposed to mild or severe hypoxia in the presence of the inhibitors. Results: Using knockdown experiments we show that PERK is essential for survival of KP4 cells while knockdown of IRE1α dramatically decreases the proliferation and survival of HCT116 during hypoxia. Further, we show that in response to both hypoxia and other ER stress-inducing agents both 4μ8c and the PERK inhibitor are selective and potent inhibitors of IRE1α and PERK activation, respectively. However, despite potent inhibition of IRE1α activation, 4μ8c had no effect on cell proliferation or clonogenic survival of cells exposed to hypoxia. This was in contrast to the inactivation of PERK signaling with the PERK inhibitor, which reduced tolerance to hypoxia and other ER stress inducing agents. Conclusions: Our results demonstrate that IRE1α but not its splicing activity is important for hypoxic cell survival. The PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress and should be the focus of future therapeutic efforts

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

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Chamberlain, Kelly A; Chapey, Kristen S; Nanescu, Sonia E; Huang, Jeffrey K

2017-02-08

Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase ( Gamt ) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt -deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

Spheroid Culture of Head and Neck Cancer Cells Reveals an Important Role of EGFR Signalling in Anchorage Independent Survival.

Science.gov (United States)

Braunholz, Diana; Saki, Mohammad; Niehr, Franziska; Öztürk, Merve; Borràs Puértolas, Berta; Konschak, Robert; Budach, Volker; Tinhofer, Ingeborg

2016-01-01

In solid tumours millions of cells are shed into the blood circulation each day. Only a subset of these circulating tumour cells (CTCs) survive, many of them presumable because of their potential to form multi-cellular clusters also named spheroids. Tumour cells within these spheroids are protected from anoikis, which allows them to metastasize to distant organs or re-seed at the primary site. We used spheroid cultures of head and neck squamous cell carcinoma (HNSCC) cell lines as a model for such CTC clusters for determining the role of the epidermal growth factor receptor (EGFR) in cluster formation ability and cell survival after detachment from the extra-cellular matrix. The HNSCC cell lines FaDu, SCC-9 and UT-SCC-9 (UT-SCC-9P) as well as its cetuximab (CTX)-resistant sub-clone (UT-SCC-9R) were forced to grow in an anchorage-independent manner by coating culture dishes with the anti-adhesive polymer poly-2-hydroxyethylmethacrylate (poly-HEMA). The extent of apoptosis, clonogenic survival and EGFR signalling under such culture conditions was evaluated. The potential of spheroid formation in suspension culture was found to be positively correlated with the proliferation rate of HNSCC cell lines as well as their basal EGFR expression levels. CTX and gefitinib blocked, whereas the addition of EGFR ligands promoted anchorage-independent cell survival and spheroid formation. Increased spheroid formation and growth were associated with persistent activation of EGFR and its downstream signalling component (MAPK/ERK). Importantly, HNSCC cells derived from spheroid cultures retained their clonogenic potential in the absence of cell-matrix contact. Addition of CTX under these conditions strongly inhibited colony formation in CTX-sensitive cell lines but not their resistant subclones. Altogether, EGFR activation was identified as crucial factor for anchorage-independent survival of HNSCC cells. Targeting EGFR in CTC cluster formation might represent an attractive anti

Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: Comparison of three methods

Energy Technology Data Exchange (ETDEWEB)

Onoda, Minori, E-mail: onoda@radt.med.kindai.ac.jp [Department of Radiological Technology, Kinki University Hospital, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942 (Japan); Hyodo, Tomoko, E-mail: neneth@m.ehime-u.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Murakami, Takamichi, E-mail: murakami@med.kindai.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Okada, Masahiro, E-mail: okada777@med.u-ryukyu.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Uto, Tatsuro, E-mail: chuho@med.kindai.ac.jp [Department of Radiological Technology, Kinki University Hospital, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Hori, Masatoshi, E-mail: mhori@radiol.med.osaka-u.ac.jp [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Miyati, Tosiaki, E-mail: ramiyati@mhs.mp.kanazawa-u.ac.jp [Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942 (Japan)

2015-03-15

Highlights: •Signal intensity is often used to evaluate hepatic enhancement with Gd-EOB-DTPA in the hepatobiliary phase. •Comparison of uncorrected signal intensity with T{sub 1} value revealed signal intensity instability. •Measurement of uncorrected liver SI or SNR often yields erroneous results on late-phase gadoxetate MRI due to shimming and other optimization techniques. •Signal intensity corrected by scale and rescale slope from DICOM data gave comparable results. -- Abstract: Objective: To compare signal intensity (SI) correction using scale and rescale slopes with SI correction using SIs of spleen and muscle for quantifying multiphase hepatic contrast enhancement with Gd-EOB-DTPA by assessing their correlation with T{sub 1} values generated from Look-Locker turbo-field-echo (LL-TFE) sequence data (ER-T{sub 1}). Materials and methods: Thirty patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in this prospective clinical study. For each patient, breath-hold T{sub 1}-weighted fat-suppressed three-dimensional (3D) gradient echo sequences (e-THRIVE) were acquired before and 2 (first phase), 10 (second phase), and 20 min (third phase) after intravenous Gd-EOB-DTPA. Look-Locker turbo-field-echo (LL-TFE) sequences were acquired before and 1.5 (first phase), 8 (second phase), and 18 min (third phase) postcontrast. The liver parenchyma enhancement ratios (ER) of each phase were calculated using the SI from e-THRIVE sequences (ER-SI) and the T{sub 1} values generated from LL-TFE sequence data (ER-T{sub 1}) respectively. ER-SIs were calculated in three ways: (1) comparing with splenic SI (ER-SI-s), (2) comparing with muscle SI (ER-SI-m), (3) using scale and rescale slopes obtained from DICOM headers (ER-SI-c), to eliminate the effects of receiver gain and scaling. For each of the first, second and third phases, correlation and agreement were assessed between each ER-SI and ER-T{sub 1}. Results: In the first phase, all ER-SIs correlated

Mitochondrial correlates of signaling processes involved with the cellular response to eimeria infection in broiler chickens

Science.gov (United States)

Host cellular responses to coccidiosis infection are consistent with elements of apoptosis, autophagy, and necrosis. These processes are enhanced in the cell through cell-directed signaling or repressed through parasite-derived inhibitors of these processes favoring the survival of the parasite. Acr...

Enhanced Global Signal of Neutral Hydrogen Due to Excess Radiation at Cosmic Dawn

Science.gov (United States)

Feng, Chang; Holder, Gilbert

2018-05-01

We revisit the global 21 cm signal calculation incorporating a possible radio background at early times, and find that the global 21 cm signal shows a much stronger absorption feature, which could enhance detection prospects for future 21 cm experiments. In light of recent reports of a possible low-frequency excess radio background, we propose that detailed 21 cm calculations should include a possible early radio background.

Adipose-derived stromal cells enhance auditory neuron survival in an animal model of sensory hearing loss.

Science.gov (United States)

Schendzielorz, Philipp; Vollmer, Maike; Rak, Kristen; Wiegner, Armin; Nada, Nashwa; Radeloff, Katrin; Hagen, Rudolf; Radeloff, Andreas

2017-10-01

A cochlear implant (CI) is an electronic prosthesis that can partially restore speech perception capabilities. Optimum information transfer from the cochlea to the central auditory system requires a proper functioning auditory nerve (AN) that is electrically stimulated by the device. In deafness, the lack of neurotrophic support, normally provided by the sensory cells of the inner ear, however, leads to gradual degeneration of auditory neurons with undesirable consequences for CI performance. We evaluated the potential of adipose-derived stromal cells (ASCs) that are known to produce neurotrophic factors to prevent neural degeneration in sensory hearing loss. For this, co-cultures of ASCs with auditory neurons have been studied, and autologous ASC transplantation has been performed in a guinea pig model of gentamicin-induced sensory hearing loss. In vitro ASCs were neuroprotective and considerably increased the neuritogenesis of auditory neurons. In vivo transplantation of ASCs into the scala tympani resulted in an enhanced survival of auditory neurons. Specifically, peripheral AN processes that are assumed to be the optimal activation site for CI stimulation and that are particularly vulnerable to hair cell loss showed a significantly higher survival rate in ASC-treated ears. ASC transplantation into the inner ear may restore neurotrophic support in sensory hearing loss and may help to improve CI performance by enhanced AN survival. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Laser Induced Breakdown Spectroscopy Based on Single Beam Splitting and Geometric Configuration for Effective Signal Enhancement

Science.gov (United States)

Yang, Guang; Lin, Qingyu; Ding, Yu; Tian, Di; Duan, Yixiang

2015-01-01

A new laser induced breakdown spectroscopy (LIBS) based on single-beam-splitting (SBS) and proper optical geometric configuration has been initially explored in this work for effective signal enhancement. In order to improve the interaction efficiency of laser energy with the ablated material, a laser beam operated in pulse mode was divided into two streams to ablate/excite the target sample in different directions instead of the conventional one beam excitation in single pulse LIBS (SP-LIBS). In spatial configuration, the laser beam geometry plays an important role in the emission signal enhancement. Thus, an adjustable geometric configuration with variable incident angle between the two splitted laser beams was constructed for achieving maximum signal enhancement. With the optimized angles of 60° and 70° for Al and Cu atomic emission lines at 396.15 nm and 324.75 nm respectively, about 5.6- and 4.8-folds signal enhancements were achieved for aluminum alloy and copper alloy samples compared to SP-LIBS. Furthermore, the temporal analysis, in which the intensity of atomic lines in SP-LIBS decayed at least ten times faster than the SBS-LIBS, proved that the energy coupling efficiency of SBS-LIBS was significantly higher than that of SP-LIBS. PMID:25557721

Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways.

Directory of Open Access Journals (Sweden)

Christina Koers-Wunrau

Full Text Available BACKGROUND: The matrix metalloproteinases (MMPs and their endogenous regulators, the tissue inhibitor of metalloproteinases (TIMPs 1-4 are responsible for the physiological remodeling of the extracellular matrix (ECM. Among all TIMPs, TIMP3 appears to play a unique role since TIMP3 is a secreted protein and, unlike the other TIMP family members, is tightly bound to the ECM. Moreover TIMP3 has been shown to be able to induce apoptotic cell death. As little is known about the underlying mechanisms, we set out to investigate the pro-apoptotic effect of TIMP3 in human mesenchymal cells. METHODOLOGY/PRINCIPAL FINDINGS: Lentiviral overexpression of TIMP3 in mesenchymal cells led to a strong dose-dependent induction of ligand-independent apoptosis as reflected by a five-fold increase in caspase 3 and 7 activity compared to control (pLenti6/V5-GW/lacZ or uninfected cells, whereas exogenous TIMP3 failed to induce apoptosis. Concordantly, increased cleavage of death substrate PARP and the caspases 3 and 7 was observed in TIMP3 overexpressing cultures. Notably, activation of caspase-8 but not caspase-9 was observed in TIMP3-overexpressing cells, indicating a death receptor-dependent mechanism. Moreover, overexpression of TIMP3 led to a further induction of apoptosis after stimulation with TNF-alpha, FasL and TRAIL. Most interestingly, TIMP3-overexpression was associated with a decrease in phosphorylation of cRaf, extracellular signal-regulated protein kinase (Erk1/2, ribosomal S6 kinase (RSK1 and Akt and serum deprivation of TIMP3-overexpressing cells resulted in a distinct enhancement of apoptosis, pointing to an impaired signaling of serum-derived survival factors. Finally, heparinase treatment of heparan sulfate proteoglycans led to the release of TIMP3 from the surface of overexpressing cells and to a significant decrease in apoptosis indicating that the binding of TIMP3 is necessary for apoptosis induction. CONCLUSION: The results demonstrate that

Signal quality enhancement using higher order wavelets for ultrasonic TOFD signals from austenitic stainless steel welds.

Science.gov (United States)

Praveen, Angam; Vijayarekha, K; Abraham, Saju T; Venkatraman, B

2013-09-01

Time of flight diffraction (TOFD) technique is a well-developed ultrasonic non-destructive testing (NDT) method and has been applied successfully for accurate sizing of defects in metallic materials. This technique was developed in early 1970s as a means for accurate sizing and positioning of cracks in nuclear components became very popular in the late 1990s and is today being widely used in various industries for weld inspection. One of the main advantages of TOFD is that, apart from fast technique, it provides higher probability of detection for linear defects. Since TOFD is based on diffraction of sound waves from the extremities of the defect compared to reflection from planar faces as in pulse echo and phased array, the resultant signal would be quite weak and signal to noise ratio (SNR) low. In many cases the defect signal is submerged in this noise making it difficult for detection, positioning and sizing. Several signal processing methods such as digital filtering, Split Spectrum Processing (SSP), Hilbert Transform and Correlation techniques have been developed in order to suppress unwanted noise and enhance the quality of the defect signal which can thus be used for characterization of defects and the material. Wavelet Transform based thresholding techniques have been applied largely for de-noising of ultrasonic signals. However in this paper, higher order wavelets are used for analyzing the de-noising performance for TOFD signals obtained from Austenitic Stainless Steel welds. It is observed that higher order wavelets give greater SNR improvement compared to the lower order wavelets. Copyright © 2013 Elsevier B.V. All rights reserved.

Transmission Property of Directly Modulated Signals Enhanced by a Micro-ring Resonator

DEFF Research Database (Denmark)

An, Yi; Lorences Riesgo, Abel; Seoane, Jorge

2012-01-01

A silicon micro-ring resonator is used to enhance the modulation speed of a 10-Gbit/s directly modulated laser to 40 Gbit/s. The generated signal is transmitted error free over 4.5 km SSMF. Dispersion tolerance is also studied....

Benefits of prescribed flows for salmon smolt survival enhancement vary longitudinally in a highly managed river system

Science.gov (United States)

Courter, Ian; Garrison, Thomas; Kock, Tobias J.; Perry, Russell W.; Child, David; Hubble, Joel

2016-01-01

The influence of streamflow on survival of emigrating juvenile Pacific salmonids Oncorhynchus spp. (smolts) is a major concern for water managers throughout the northeast Pacific Rim. However, few studies have quantified flow effects on smolt survival, and available information does not indicate a consistent flow–survival relationship within the typical range of flows under management control. In the Yakima Basin, Washington, the potential effects of streamflow alterations on smolt survival have been debated for over 20 years. Using a series of controlled flow releases from upper basin reservoirs and radiotelemetry, we quantified the relationship between flow and yearling Chinook salmon smolt survival in the 208 km reach between Roza Dam and the Yakima River mouth. A multistate mark–recapture model accounted for weekly variation in flow conditions experienced by tagged fish in four discrete river segments. Smolt survival was significantly associated with streamflow in the Roza Reach [river kilometre (rkm) 208–189] and marginally associated with streamflow in the Sunnyside Reach (rkm 169–77). However, smolt survival was not significantly associated with flow in the Naches and Prosser Reaches (rkm 189–169 and rkm 77–3). This discrepancy indicates potential differences in underlying flow-related survival mechanisms, such as predation or passage impediments. Our results clarify trade-offs between flow augmentation for fisheries enhancement and other beneficial uses, and our study design provides a framework for resolving uncertainties about streamflow effects on migratory fish survival in other river systems. 

High-resolution blood-pool-contrast-enhanced MR angiography in glioblastoma: tumor-associated neovascularization as a biomarker for patient survival. A preliminary study

Energy Technology Data Exchange (ETDEWEB)

Puig, Josep; Blasco, Gerard; Remollo, Sebastian; Hernandez, David; Pedraza, Salvador [Hospital Universitari Dr Josep Trueta, Research Unit of Diagnostic Imaging Institute (IDI), Department of Radiology [Girona Biomedical Research Institute] IDIBGI, Girona (Spain); Daunis-i-Estadella, Josep; Mateu, Gloria [University of Girona, Department of Computer Science, Applied Mathematics and Statistics, Girona (Spain); Alberich-Bayarri, Angel [La Fe Polytechnics and University Hospital, Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, Valencia (Spain); Essig, Marco [University of Manitoba, Department of Radiology, Winnipeg (Canada); Jain, Rajan [NYU School of Medicine, Division of Neuroradiology, Department of Radiology, New York, NY (United States); Puigdemont, Montserrat [Hospital Universitari Dr Josep Trueta, Catalan Institute of Oncology (ICO), Hospital Cancer Registry, Girona (Spain); Sanchez-Gonzalez, Javier [Philips Healthcare Iberica, Madrid (Spain); Wintermark, Max [Stanford University, Department of Radiology, Neuroradiology Division, Palo Alto, CA (United States)

2016-01-15

The objective of the study was to determine whether tumor-associated neovascularization on high-resolution gadofosveset-enhanced magnetic resonance angiography (MRA) is a useful biomarker for predicting survival in patients with newly diagnosed glioblastomas. Before treatment, 35 patients (25 men; mean age, 64 ± 14 years) with glioblastoma underwent MRI including first-pass dynamic susceptibility contrast (DSC) perfusion and post-contrast T1WI sequences with gadobutrol (0.1 mmol/kg) and, 48 h later, high-resolution MRA with gadofosveset (0.03 mmol/kg). Volumes of interest for contrast-enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter were obtained, and DSC perfusion and DWI parameters were evaluated. Prognostic factors were assessed by Kaplan-Meier survival and Cox proportional hazards model. Eighteen (51.42 %) glioblastomas were hypervascular on high-resolution MRA. Hypervascular glioblastomas were associated with higher CEL volume and lower Karnofsky score. Median survival rates for patients with hypovascular and hypervascular glioblastomas treated with surgery, radiotherapy, and chemotherapy were 15 and 9.75 months, respectively (P < 0.001). Tumor-associated neovascularization was the best predictor of survival at 5.25 months (AUC = 0.794, 81.2 % sensitivity, 77.8 % specificity, 76.5 % positive predictive value, 82.4 % negative predictive value) and yielded the highest hazard ratio (P < 0.001). Tumor-associated neovascularization detected on high-resolution blood-pool-contrast-enhanced MRA of newly diagnosed glioblastoma seems to be a useful biomarker that correlates with worse survival. (orig.)

Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum.

Directory of Open Access Journals (Sweden)

Jose C Garcia-Garcia

2009-06-01

Full Text Available Intracellular bacteria have evolved mechanisms that promote survival within hostile host environments, often resulting in functional dysregulation and disease. Using the Anaplasma phagocytophilum-infected granulocyte model, we establish a link between host chromatin modifications, defense gene transcription and intracellular bacterial infection. Infection of THP-1 cells with A. phagocytophilum led to silencing of host defense gene expression. Histone deacetylase 1 (HDAC1 expression, activity and binding to the defense gene promoters significantly increased during infection, which resulted in decreased histone H3 acetylation in infected cells. HDAC1 overexpression enhanced infection, whereas pharmacologic and siRNA HDAC1 inhibition significantly decreased bacterial load. HDAC2 does not seem to be involved, since HDAC2 silencing by siRNA had no effect on A. phagocytophilum intracellular propagation. These data indicate that HDAC up-regulation and epigenetic silencing of host cell defense genes is required for A. phagocytophilum infection. Bacterial epigenetic regulation of host cell gene transcription could be a general mechanism that enhances intracellular pathogen survival while altering cell function and promoting disease.

Downhole microseismic signal-to-noise ratio enhancement via strip matching shearlet transform

Science.gov (United States)

Li, Juan; Ji, Shuo; Li, Yue; Qian, Zhihong; Lu, Weili

2018-04-01

Shearlet transform has been proved effective in noise attenuation. However, because of the low magnitude and high frequency of downhole microseismic signals, the coefficient values of valid signals and noise are similar in the shearlet domain. As a result, it is hard to suppress the noise. In this paper, we present a novel signal-to-noise ratio enhancement scheme called strip matching shearlet transform. The method takes into account the directivity of microseismic events and shearlets. Through strip matching, the matching degree in direction between them has been promoted. Then the coefficient values of valid signals are much larger than those of the noise. Consequently, we can separate them well with the help of thresholding. The experimental results on both synthetic records and field data illustrate that our proposed method preserves the useful components and attenuates the noise well.

A biological inspired fuzzy adaptive window median filter (FAWMF) for enhancing DNA signal processing.

Science.gov (United States)

Ahmad, Muneer; Jung, Low Tan; Bhuiyan, Al-Amin

2017-10-01

Digital signal processing techniques commonly employ fixed length window filters to process the signal contents. DNA signals differ in characteristics from common digital signals since they carry nucleotides as contents. The nucleotides own genetic code context and fuzzy behaviors due to their special structure and order in DNA strand. Employing conventional fixed length window filters for DNA signal processing produce spectral leakage and hence results in signal noise. A biological context aware adaptive window filter is required to process the DNA signals. This paper introduces a biological inspired fuzzy adaptive window median filter (FAWMF) which computes the fuzzy membership strength of nucleotides in each slide of window and filters nucleotides based on median filtering with a combination of s-shaped and z-shaped filters. Since coding regions cause 3-base periodicity by an unbalanced nucleotides' distribution producing a relatively high bias for nucleotides' usage, such fundamental characteristic of nucleotides has been exploited in FAWMF to suppress the signal noise. Along with adaptive response of FAWMF, a strong correlation between median nucleotides and the Π shaped filter was observed which produced enhanced discrimination between coding and non-coding regions contrary to fixed length conventional window filters. The proposed FAWMF attains a significant enhancement in coding regions identification i.e. 40% to 125% as compared to other conventional window filters tested over more than 250 benchmarked and randomly taken DNA datasets of different organisms. This study proves that conventional fixed length window filters applied to DNA signals do not achieve significant results since the nucleotides carry genetic code context. The proposed FAWMF algorithm is adaptive and outperforms significantly to process DNA signal contents. The algorithm applied to variety of DNA datasets produced noteworthy discrimination between coding and non-coding regions contrary

TLR-4/miRNA-32-5p/FSTL1 signaling regulates mycobacterial survival and inflammatory responses in Mycobacterium tuberculosis-infected macrophages.

Science.gov (United States)

Zhang, Zhi-Min; Zhang, Ai-Rong; Xu, Min; Lou, Jun; Qiu, Wei-Qiang

2017-03-15

Macrophages play a pivotal role in host immune response against mycobacterial infection, which is tightly modulated by multiple factors, including microRNAs. The purpose of the present study was to investigate the biological function and potential mechanism of miR-32-5p in human macrophages during Mycobacterium tuberculosis (M.tb) infection. The results demonstrated that miR-32-5p was robustly enhanced in THP-1 and U937 cells in response to M.tb infection. TLR-4 signaling was required for upregulation of miR-32-5p induced by M.tb infection. Additionally, the introduction of miR-32-5p strongly increased the survival rate of intracellular mycobacteria, whereas inhibition of miR-32-5p suppressed intracellular growth of mycobacteria during M.tb challenged. Furthermore, forced expression of miR-32-5p dramatically attenuated the accumulation of inflammatory cytokines IL-1β, IL-6 and TNF-α induced by M.tb infection. Conversely, downregulated expression of miR-32-5p led to enhancement in these inflammatory cytokines. More importantly, our study explored that Follistatin-like protein 1 (FSTL1) was a direct and functional target of miR-32-5p. qRT-PCR and western blot analysis further validated that miR-32-5p negatively regulated the expression of FSTL1. Mechanistically, re-expression of FSTL1 attenuated the ability of miR-32-5p to promote mycobacterial survival. Meanwhile, miR-32-5p-mediated inhibition of the inflammatory cytokine production were completely reversed by overexpression of FSTL1. Collectively, our findings demonstrated a novel role of TLR-4/miRNA-32-5p/FSTL1 in the modulation of host defense against mycobacterial infection, which may provide a better understanding of the pathogenesis of tuberculosis and useful information for developing potential therapeutic interventions against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuropilin-2 mediated β-catenin signaling and survival in human gastro-intestinal cancer cell lines.

Directory of Open Access Journals (Sweden)

Shaija Samuel

Full Text Available NRP-2 is a high-affinity kinase-deficient receptor for ligands belonging to the class 3 semaphorin and vascular endothelial growth factor families. NRP-2 has been detected on the surface of several types of human cancer cells, but its expression and function in gastrointestinal (GI cancer cells remains to be determined. We sought to determine the function of NRP-2 in mediating downstream signals regulating the growth and survival of human gastrointestinal cancer cells. In human gastric cancer specimens, NRP-2 expression was detected in tumor tissues but not in adjacent normal mucosa. In CNDT 2.5 cells, shRNA mediated knockdown NRP-2 expression led to decreased migration and invasion in vitro (p<0.01. Focused gene-array analysis demonstrated that loss of NRP-2 reduced the expression of a critical metastasis mediator gene, S100A4. Steady-state levels and function of β-catenin, a known regulator of S100A4, were also decreased in the shNRP-2 clones. Furthermore, knockdown of NRP-2 sensitized CNDT 2.5 cells in vitro to 5FU toxicity. This effect was associated with activation of caspases 3 and 7, cleavage of PARP, and downregulation of Bcl-2. In vivo growth of CNDT 2.5 cells in the livers of nude mice was significantly decreased in the shNRP-2 group (p<0.05. Intraperitoneal administration of NRP-2 siRNA-DOPC decreased the tumor burden in mice (p = 0.01. Collectively, our results demonstrate that tumor cell-derived NRP-2 mediates critical survival signaling in gastrointestinal cancer cells.

Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit

International Nuclear Information System (INIS)

Raju, Uma; Molkentine, David P; Valdecanas, David R; Deorukhkar, Amit; Mason, Kathryn A; Buchholz, Thomas A; Meyn, Raymond E; Ang, Kie-Kian; Skinner, Heath

2015-01-01

Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC-A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ-H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC-A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ-H2AX and 53BP1 foci. IMC-A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. Addition of IMC-A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC-A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT

Mine detection using SF-GPR: A signal processing approach for resolution enhancement and clutter reduction

DEFF Research Database (Denmark)

Karlsen, Brian; Jakobsen, Kaj Bjarne; Larsen, Jan

2001-01-01

Proper clutter reduction is essential for Ground Penetrating Radar data since low signal-to-clutter ratio prevent correct detection of mine objects. A signal processing approach for resolution enhancement and clutter reduction used on Stepped-Frequency Ground Penetrating Radar (SF-GPR) data is pr....... The clutter reduction method is based on basis function decomposition of the SF-GPR time-series from which the clutter and the signal are separated....

Use and Protection of GPS Sidelobe Signals for Enhanced Navigation Performance in High Earth Orbit

Science.gov (United States)

Parker, Joel J. K.; Valdez, Jennifer E.; Bauer, Frank H.; Moreau, Michael C.

2016-01-01

GPS (Global Positioning System) Space Service Volume (SSV) signal environment is from 3,000-36,000 kilometers altitude. Current SSV specifications only capture performance provided by signals transmitted within 23.5(L1) or 26(L2-L5) off-nadir angle. Recent on-orbit data lessons learned show significant PNT (Positioning, Navigation and Timing) performance improvements when the full aggregate signal is used. Numerous military civil operational missions in High Geosynchronous Earth Orbit (HEOGEO) utilize the full signal to enhance vehicle PNT performance

Using neural networks to enhance the Higgs boson signal at hadron colliders

International Nuclear Information System (INIS)

Field, R.D.; Kanev, Y.; Tayebnejad, M.; Griffin, P.A.

1995-01-01

Neural networks are used to help distinguish the ZZ → ell + ell - -jet-jet signal produced by the decay of a 400 GeV Higgs boson at a proton-proton collider energy of 15 TeV from the ''ordinary'' QCD Z + jets background. The ideal case where only one event at a time enters the detector (no pile-up) and the case of multiple interactions per beam crossing (pile-up) are examined. In both cases, when used in conjunction with the standard cuts, neural networks provide an additional signal to background enhancement

Select polyphenolic fractions from dried plum enhance osteoblast activity through BMP-2 signaling.

Science.gov (United States)

Graef, Jennifer L; Rendina-Ruedy, Elizabeth; Crockett, Erica K; Ouyang, Ping; King, Jarrod B; Cichewicz, Robert H; Lucas, Edralin A; Smith, Brenda J

2018-05-01

Dried plum supplementation has been shown to enhance bone formation while suppressing bone resorption. Evidence from previous studies has demonstrated that these responses can be attributed in part to the fruit's polyphenolic compounds. The purpose of this study was to identify the most bioactive polyphenolic fractions of dried plum with a focus on their osteogenic activity and to investigate their mechanisms of action under normal and inflammatory conditions. Utilizing chromatographic techniques, six fractions of polyphenolic compounds were prepared from a crude extract of dried plum. Initial screening assays revealed that two fractions (DP-FrA and DP-FrB) had the greatest osteogenic potential. Subsequent experiments using primary bone-marrow-derived osteoblast cultures demonstrated these two fractions enhanced extracellular alkaline phosphatase (ALP), an indicator of osteoblast activity, and mineralized nodule formation under normal conditions. Both fractions enhanced bone morphogenetic protein (BMP) signaling, as indicated by increased Bmp2 and Runx2 gene expression and protein levels of phosphorylated Smad1/5. DP-FrB was most effective at up-regulating Tak1 and Smad1, as well as protein levels of phospho-p38. Under inflammatory conditions, TNF-α suppressed ALP and tended to decrease nodule formation (P=.0674). This response coincided with suppressed gene expression of Bmp2 and the up-regulation of Smad6, an inhibitor of BMP signaling. DP-FrA and DP-FrB partially normalized these responses. Our results show that certain fractions of polyphenolic compounds in dried plum up-regulate osteoblast activity by enhancing BMP signaling, and when this pathway is inhibited by TNF-α, the osteogenic response is attenuated. Copyright © 2017 Elsevier Inc. All rights reserved.

Cyclophilin B Supports Myc and Mutant p53 Dependent Survival of Glioblastoma Multiforme Cells

Science.gov (United States)

Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N.; Bram, Richard J.

2014-01-01

Glioblastoma multiforme (GBM) is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in GBM cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human GBM cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of GBM cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-MAPK pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1 and JAK/STAT3 signaling. Elevated reactive oxygen species, ER expansion and abnormal unfolded protein responses in CypB-depleted GBM cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of GBM tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for GBM therapy. PMID:24272483

Top layer enhances biological ontrol of thrips in ornamentals :"Predatory mites survive better on rich soil cover

NARCIS (Netherlands)

Hoogstraten, van K.; Grosman, A.H.

2014-01-01

An organic top layer over the soil or substrate can enhance the biological control of thrips in roses and alstroemerias. The top layer contains food for prey mites, which in turn serve as food for predatory mites. In this way the predators survive longer. Thus, as the thrips population increases, an

Effect of microbubble ligation to cells on ultrasound signal enhancement: implications for targeted imaging.

Science.gov (United States)

Lankford, Miles; Behm, Carolyn Z; Yeh, James; Klibanov, Alexander L; Robinson, Peter; Lindner, Jonathan R

2006-10-01

Molecular imaging with contrast-enhanced ultrasound (CEU) relies on the detection of microbubbles retained in regions of disease. The aim of this study was to determine whether microbubble attachment to cells influences their acoustic signal generation and stability. Biotinylated microbubbles were attached to streptavidin-coated plates to derive density versus intensity relations during low- and high-power imaging. To assess damping from microbubble attachment to solid or cell surfaces, in vitro imaging was performed for microbubbles charge-coupled to methacrylate spheres and for vascular cell adhesion molecule-1-targeted microbubbles attached to endothelial cells. Signal enhancement on plates increased according to acoustic power and microbubble site density up to 300 mm. Microbubble signal was reduced by attachment to solid spheres during high- and low-power imaging but was minimally reduced by attachment to endothelial cells and only at low power. Attachment of targeted microbubbles to rigid surfaces results in damping and a reduction of their acoustic signal, which is not seen when microbubbles are attached to cells. A reliable concentration versus intensity relationship can be expected from microbubble attachment to 2-dimensional surfaces until a very high site density is reached.

Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

Science.gov (United States)

McGraw, Kathy L; Basiorka, Ashley A; Johnson, Joseph O; Clark, Justine; Caceres, Gisela; Padron, Eric; Heaton, Ruth; Ozawa, Yukiyasu; Wei, Sheng; Sokol, Lubomir; List, Alan F

2014-01-01

Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS). Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR) signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size). Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q) MDS.

Enhancement of new physics signal sensitivity with mistagged charm quarks

Directory of Open Access Journals (Sweden)

Doojin Kim

2016-07-01

Full Text Available We investigate the potential for enhancing search sensitivity for signals having charm quarks in the final state, using the sizable bottom-mistagging rate for charm quarks at the LHC. Provided that the relevant background processes contain light quarks instead of charm quarks, the application of b-tagging on charm quark-initiated jets enables us to reject more background events than signal ones due to the relatively small mistagging rate for light quarks. The basic idea is tested with two rare top decay processes: i t→ch→cbb¯ and ii t→bH+→bb¯c where h and H+ denote the Standard Model-like higgs boson and a charged higgs boson, respectively. The major background source is a hadronic top quark decay such as t→bW+→bs¯c. We test our method with Monte Carlo simulation at the LHC 14 TeV, and find that the signal-over-background ratio can be increased by a factor of O(6–7 with a suitably designed (heavy flavor tagging algorithm and scheme.

Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.

Science.gov (United States)

Katare, Rajesh; Caporali, Andrea; Emanueli, Costanza; Madeddu, Paolo

2010-10-01

Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia. Copyright © 2010 Elsevier Ltd. All rights reserved.

TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway.

Science.gov (United States)

Zhang, L-H; Yin, A-A; Cheng, J-X; Huang, H-Y; Li, X-M; Zhang, Y-Q; Han, N; Zhang, X

2015-01-29

The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3-kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-κB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas.

Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice.

Science.gov (United States)

Freitas, Andiara E; Bettio, Luis E B; Neis, Vivian B; Moretti, Morgana; Ribeiro, Camille M; Lopes, Mark W; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

2014-11-01

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001-0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237-258% of control), protein kinase B/Akt (Ser(473)) (116-127% of control), glycogen synthase kinase-3β (Ser(9)) (110-113% of control), extracellular signal-regulated kinases 1/2 (119-137% and 121-138% of control, respectively) and cAMP response elements (Ser(133)) (127-152% of control), and brain-derived-neurotrophic factor (137-175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001-0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38(MAPK) phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus. Copyright © 2014 Elsevier Ltd. All rights reserved.

METHODS FOR QUALITY ENHANCEMENT OF USER VOICE SIGNAL IN VOICE AUTHENTICATION SYSTEMS

Directory of Open Access Journals (Sweden)

O. N. Faizulaieva

2014-03-01

Full Text Available The reasonability for the usage of computer systems user voice in the authentication process is proved. The scientific task for improving the signal/noise ratio of the user voice signal in the authentication system is considered. The object of study is the process of input and output of the voice signal of authentication system user in computer systems and networks. Methods and means for input and extraction of voice signal against external interference signals are researched. Methods for quality enhancement of user voice signal in voice authentication systems are suggested. As modern computer facilities, including mobile ones, have two-channel audio card, the usage of two microphones is proposed in the voice signal input system of authentication system. Meanwhile, the task of forming a lobe of microphone array in a desired area of voice signal registration (100 Hz to 8 kHz is solved. The usage of directional properties of the proposed microphone array gives the possibility to have the influence of external interference signals two or three times less in the frequency range from 4 to 8 kHz. The possibilities for implementation of space-time processing of the recorded signals using constant and adaptive weighting factors are investigated. The simulation results of the proposed system for input and extraction of signals during digital processing of narrowband signals are presented. The proposed solutions make it possible to improve the value of the signal/noise ratio of the useful signals recorded up to 10, ..., 20 dB under the influence of external interference signals in the frequency range from 4 to 8 kHz. The results may be useful to specialists working in the field of voice recognition and speaker’s discrimination.

Efficient Techniques of Sparse Signal Analysis for Enhanced Recovery of Information in Biomedical Engineering and Geosciences

KAUST Repository

Sana, Furrukh

2016-11-01

Sparse signals are abundant among both natural and man-made signals. Sparsity implies that the signal essentially resides in a small dimensional subspace. The sparsity of the signal can be exploited to improve its recovery from limited and noisy observations. Traditional estimation algorithms generally lack the ability to take advantage of signal sparsity. This dissertation considers several problems in the areas of biomedical engineering and geosciences with the aim of enhancing the recovery of information by exploiting the underlying sparsity in the problem. The objective is to overcome the fundamental bottlenecks, both in terms of estimation accuracies and required computational resources. In the first part of dissertation, we present a high precision technique for the monitoring of human respiratory movements by exploiting the sparsity of wireless ultra-wideband signals. The proposed technique provides a novel methodology of overcoming the Nyquist sampling constraint and enables robust performance in the presence of noise and interferences. We also present a comprehensive framework for the important problem of extracting the fetal electrocardiogram (ECG) signals from abdominal ECG recordings of pregnant women. The multiple measurement vectors approach utilized for this purpose provides an efficient mechanism of exploiting the common structure of ECG signals, when represented in sparse transform domains, and allows leveraging information from multiple ECG electrodes under a joint estimation formulation. In the second part of dissertation, we adopt sparse signal processing principles for improved information recovery in large-scale subsurface reservoir characterization problems. We propose multiple new algorithms for sparse representation of the subsurface geological structures, incorporation of useful prior information in the estimation process, and for reducing computational complexities of the problem. The techniques presented here enable significantly

Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation.

Science.gov (United States)

Mak, Kingston Kinglun; Chen, Miao-Hsueh; Day, Timothy F; Chuang, Pao-Tien; Yang, Yingzi

2006-09-01

Both the Wnt/beta-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated the beta-catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using beta-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/beta-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. Beta-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, beta-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. However, there is a strong synergistic interaction between Wnt/beta-catenin and Ihh signaling in regulating synovial joint formation.

Tuning plant signaling and growth to survive salt

NARCIS (Netherlands)

Julkowska, M.M.; Testerink, C.

2015-01-01

Salinity is one of the major abiotic factors threatening food security worldwide. Recently, our understanding of early processes underlying salinity tolerance has expanded. In this review, early signaling events, such as phospholipid signaling, calcium ion (Ca(2+)) responses, and reactive oxygen

Enhancement of the automatic ultrasonic signal processing system using digital technology

International Nuclear Information System (INIS)

Koo, In Soo; Park, H. Y.; Suh, Y. S.; Kim, D. Hoon; Huh, S.; Sung, S. H.; Jang, G. S.; Ryoo, S. G.; Choi, J. H.; Kim, Y. H.; Lee, J. C.; Kim, D. Hyun; Park, H. J.; Kim, Y. C.; Lee, J. P.; Park, C. H.; Kim, M. S.

1999-12-01

The objective of this study is to develop the automatic ultrasonic signal processing system which can be used in the inspection equipment to assess the integrity of the reactor vessel by enhancing the performance of the ultrasonic signal processing system. Main activities of this study divided into three categories such as the development of the circuits for generating ultrasonic signal and receiving the signal from the inspection equipment, the development of signal processing algorithm and H/W of the data processing system, and the development of the specification for application programs and system S/W for the analysis and evaluation computer. The results of main activities are as follows 1) the design of the ultrasonic detector and the automatic ultrasonic signal processing system by using the investigation of the state-of-the-art technology in the inside and outside of the country. 2) the development of H/W and S/W of the data processing system based on the results. Especially, the H/W of the data processing system, which have both advantages of digital and analog controls through the real-time digital signal processing, was developed using the DSP which can process the digital signal in the real-time, and was developed not only firmware of the data processing system in order for the peripherals but also the test algorithm of specimen for the calibration. The application programs and the system S/W of the analysis/evaluation computer were developed. Developed equipment was verified by the performance test. Based on developed prototype for the automatic ultrasonic signal processing system, the localization of the overall ultrasonic inspection equipment for nuclear industries would be expected through the further studies of the H/W establishment of real applications, developing the S/W specification of the analysis computer. (author)

The ShcA SH2 domain engages a 14-3-3/PI3'K signaling complex and promotes breast cancer cell survival.

Science.gov (United States)

Ursini-Siegel, J; Hardy, W R; Zheng, Y; Ling, C; Zuo, D; Zhang, C; Podmore, L; Pawson, T; Muller, W J

2012-11-29

The ShcA adapter protein transmits activating signals downstream of receptor and cytoplasmic tyrosine kinases through the establishment of phosphotyrosine-dependent complexes. In this regard, ShcA possesses both a phosphotyrosine-binding domain (PTB) and Src homology 2 domain (SH2), which bind phosphotyrosine residues in a sequence-specific manner. Although the majority of receptor tyrosine kinases expressed in breast cancer cells bind the PTB domain, very little is known regarding the biological importance of SH2-driven ShcA signaling during mammary tumorigenesis. To address this, we employed transgenic mice expressing a mutant ShcA allele harboring a non-functional SH2 domain (ShcR397K) under the transcriptional control of the endogenous ShcA promoter. Using transplantation approaches, we demonstrate that SH2-dependent ShcA signaling within the mammary epithelial compartment is essential for breast tumor outgrowth, survival and the development of lung metastases. We further show that the ShcA SH2 domain activates the AKT pathway, potentially through a novel SH2-mediated complex between ShcA, 14-3-3ζ and the p85 regulatory subunit of phosphatidylinositol 3 (PI3') kinase. This study is the first to demonstrate that the SH2 domain of ShcA is critical for tumor survival during mammary tumorigenesis.

MR imaging of renal cell carcinoma. Associations among signal intensity, tumor enhancement, and pathologic findings

Energy Technology Data Exchange (ETDEWEB)

Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio [Okayama Univ. (Japan). Graduate School of Medicine and Dentistry

2003-08-01

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation. (author)

MR imaging of renal cell carcinoma. Associations among signal intensity, tumor enhancement, and pathologic findings

International Nuclear Information System (INIS)

Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio

2003-01-01

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation. (author)

Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells.

Science.gov (United States)

Ramakrishnan, P; Kahn, D A; Baltimore, D

2011-04-01

Thymocyte development is a tightly controlled multi-step process involving selective elimination of self-reactive and non-functional T cells by apoptosis. This developmental process depends on signaling by Notch, IL-7 and active glucose metabolism. In this study, we explored the requirement of glucose for thymocyte survival and found that in addition to metabolic regulation, glucose leads to the expression of anti-apoptotic genes. Under hyperglycemic conditions, both mouse and human thymocytes demonstrate enhanced survival. We show that glucose-induced anti-apoptotic genes are dependent on NF-κB p65 because high glucose is unable to attenuate normal ongoing apoptosis of thymocytes isolated from p65 knockout mice. Furthermore, we demonstrate that in vivo hyperglycemia decreases apoptosis of thymocytes allowing for survival of potentially self-reactive thymocytes. These results imply that hyperglycemic conditions could contribute to the development of autoimmunity through dysregulated thymic selection. © 2011 Macmillan Publishers Limited

IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling.

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Timper, Katharina; Denson, Jesse Lee; Steculorum, Sophie Marie; Heilinger, Christian; Engström-Ruud, Linda; Wunderlich, Claudia Maria; Rose-John, Stefan; Wunderlich, F Thomas; Brüning, Jens Claus

2017-04-11

Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling

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Katharina Timper

2017-04-01

Full Text Available Interleukin (IL-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

Science.gov (United States)

Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

2016-04-01

The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. © FASEB.

The BTK Inhibitor Ibrutinib (PCI-32765) Blocks Hairy Cell Leukaemia Survival, Proliferation and BCR Signalling: A New Therapeutic Approach

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Sivina, Mariela; Kreitman, Robert J.; Arons, Evgeny; Ravandi, Farhad; Burger, Jan A.

2014-01-01

B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins (A, G, and M) and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL. PMID:24697238

Correlation dynamics and enhanced signals for the identification of serial biomolecules and DNA bases

International Nuclear Information System (INIS)

Ahmed, Towfiq; Haraldsen, Jason T; Balatsky, Alexander V; Rehr, John J; Di Ventra, Massimiliano; Schuller, Ivan

2014-01-01

Nanopore-based sequencing has demonstrated a significant potential for the development of fast, accurate, and cost-efficient fingerprinting techniques for next generation molecular detection and sequencing. We propose a specific multilayered graphene-based nanopore device architecture for the recognition of single biomolecules. Molecular detection and analysis can be accomplished through the detection of transverse currents as the molecule or DNA base translocates through the nanopore. To increase the overall signal-to-noise ratio and the accuracy, we implement a new ‘multi-point cross-correlation’ technique for identification of DNA bases or other molecules on the single molecular level. We demonstrate that the cross-correlations between each nanopore will greatly enhance the transverse current signal for each molecule. We implement first-principles transport calculations for DNA bases surveyed across a multilayered graphene nanopore system to illustrate the advantages of the proposed geometry. A time-series analysis of the cross-correlation functions illustrates the potential of this method for enhancing the signal-to-noise ratio. This work constitutes a significant step forward in facilitating fingerprinting of single biomolecules using solid state technology. (paper)

Correlation dynamics and enhanced signals for the identification of serial biomolecules and DNA bases

Science.gov (United States)

Ahmed, Towfiq; Haraldsen, Jason T.; Rehr, John J.; Di Ventra, Massimiliano; Schuller, Ivan; Balatsky, Alexander V.

2014-03-01

Nanopore-based sequencing has demonstrated a significant potential for the development of fast, accurate, and cost-efficient fingerprinting techniques for next generation molecular detection and sequencing. We propose a specific multilayered graphene-based nanopore device architecture for the recognition of single biomolecules. Molecular detection and analysis can be accomplished through the detection of transverse currents as the molecule or DNA base translocates through the nanopore. To increase the overall signal-to-noise ratio and the accuracy, we implement a new ‘multi-point cross-correlation’ technique for identification of DNA bases or other molecules on the single molecular level. We demonstrate that the cross-correlations between each nanopore will greatly enhance the transverse current signal for each molecule. We implement first-principles transport calculations for DNA bases surveyed across a multilayered graphene nanopore system to illustrate the advantages of the proposed geometry. A time-series analysis of the cross-correlation functions illustrates the potential of this method for enhancing the signal-to-noise ratio. This work constitutes a significant step forward in facilitating fingerprinting of single biomolecules using solid state technology.

Zcchc11 Uridylates Mature miRNAs to Enhance Neonatal IGF-1 Expression, Growth, and Survival

Science.gov (United States)

Kozlowski, Elyse; Matsuura, Kori Y.; Ferrari, Joseph D.; Morris, Samantha A.; Powers, John T.; Daley, George Q.; Quinton, Lee J.; Mizgerd, Joseph P.

2012-01-01

The Zcchc11 enzyme is implicated in microRNA (miRNA) regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3′ terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression. PMID:23209448

Zcchc11 uridylates mature miRNAs to enhance neonatal IGF-1 expression, growth, and survival.

Directory of Open Access Journals (Sweden)

Matthew R Jones

Full Text Available The Zcchc11 enzyme is implicated in microRNA (miRNA regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3' terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression.

Genetic modification of embryonic stem cells with VEGF enhances cell survival and improves cardiac function.

Science.gov (United States)

Xie, Xiaoyan; Cao, Feng; Sheikh, Ahmad Y; Li, Zongjin; Connolly, Andrew J; Pei, Xuetao; Li, Ren-Ke; Robbins, Robert C; Wu, Joseph C

2007-01-01

Cardiac stem cell therapy remains hampered by acute donor cell death posttransplantation and the lack of reliable methods for tracking cell survival in vivo. We hypothesize that cells transfected with inducible vascular endothelial growth factor 165 (VEGF(165)) can improve their survival as monitored by novel molecular imaging techniques. Mouse embryonic stem (ES) cells were transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF(165) and renilla luciferase (Rluc). Addition of doxycycline induced Bi-Tet expression of VEGF(165) and Rluc significantly compared to baseline (p<0.05). Expression of VEGF(165) enhanced ES cell proliferation and inhibited apoptosis as determined by Annexin-V staining. For noninvasive imaging, ES cells were transduced with a double fusion (DF) reporter gene consisting of firefly luciferase and enhanced green fluorescence protein (Fluc-eGFP). There was a robust correlation between cell number and Fluc activity (R(2)=0.99). Analysis by immunostaining, histology, and RT-PCR confirmed that expression of Bi-Tet and DF systems did not affect ES cell self-renewal or pluripotency. ES cells were differentiated into beating embryoid bodies expressing cardiac markers such as troponin, Nkx2.5, and beta-MHC. Afterward, 5 x 10(5) cells obtained from these beating embryoid bodies or saline were injected into the myocardium of SV129 mice (n=36) following ligation of the left anterior descending (LAD) artery. Bioluminescence imaging (BLI) and echocardiography showed that VEGF(165) induction led to significant improvements in both transplanted cell survival and cardiac function (p<0.05). This is the first study to demonstrate imaging of embryonic stem cell-mediated gene therapy targeting cardiovascular disease. With further validation, this platform may have broad applications for current basic research and further clinical studies.

Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells

Directory of Open Access Journals (Sweden)

Wolff Natascha A

2010-05-01

Full Text Available Abstract Background The class 1 carcinogen cadmium (Cd2+ disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis. Results We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC. Cd2+ (25 μM, 3-9 h caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1 were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability. Conclusions Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.

The application of empirical mode decomposition for the enhancement of cardiotocograph signals

International Nuclear Information System (INIS)

Krupa, B N; Mohd Ali, M A; Zahedi, E

2009-01-01

Cardiotocograph (CTG) is widely used in everyday clinical practice for fetal surveillance, where it is used to record fetal heart rate (FHR) and uterine activity (UA). These two biosignals can be used for antepartum and intrapartum fetal monitoring and are, in fact, nonlinear and non-stationary. CTG recordings are often corrupted by artifacts such as missing beats in FHR, high-frequency noise in FHR and UA signals. In this paper, an empirical mode decomposition (EMD) method is applied on CTG signals. A recursive algorithm is first utilized to eliminate missing beats. High-frequency noise is reduced using EMD followed by the partial reconstruction (PAR) method, where the noise order is identified by a statistical method. The obtained signal enhancement from the proposed method is validated by comparing the resulting traces with the output obtained by applying classical signal processing methods such as Butterworth low-pass filtering, linear interpolation and a moving average filter on 12 CTG signals. Three obstetricians evaluated all 12 sets of traces and rated the proposed method, on average, 3.8 out of 5 on a scale of 1(lowest) to 5 (highest)

Does colour polymorphism enhance survival of prey populations?

Science.gov (United States)

Wennersten, Lena; Forsman, Anders

2009-01-01

That colour polymorphism may protect prey populations from predation is an old but rarely tested hypothesis. We examine whether colour polymorphic populations of prey exposed to avian predators in an ecologically valid visual context were exposed to increased extinction risk compared with monomorphic populations. We made 2976 artificial pastry prey, resembling Lepidoptera larvae, in four different colours and presented them in 124 monomorphic and 124 tetramorphic populations on tree trunks and branches such that they would be exposed to predation by free-living birds, and monitored their ‘survival’. Among monomorphic populations, there was a significant effect of prey coloration on survival, confirming that coloration influenced susceptibility to visually oriented predators. Survival of polymorphic populations was inferior to that of monomorphic green populations, but did not differ significantly from monomorphic brown, yellow or red populations. Differences in survival within polymorphic populations paralleled those seen among monomorphic populations; the red morph most frequently went extinct first and the green morph most frequently survived the longest. Our findings do not support the traditional protective polymorphism hypothesis and are in conflict with those of earlier studies. As a possible explanation to our findings, we offer a competing ‘giveaway cue’ hypothesis: that polymorphic populations may include one morph that attracts the attention of predators and that polymorphic populations therefore may suffer increased predation compared with some monomorphic populations. PMID:19324729

Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.

Science.gov (United States)

Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N; Bram, Richard J

2014-01-15

Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.

Raman signal enhancement by multiple beam excitation and its application for the detection of chemicals

Energy Technology Data Exchange (ETDEWEB)

Gupta, Sakshi [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India); Instrument Design and Development Centre, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Ahmad, Azeem; Mehta, Dalip S., E-mail: mehtads@physics.iitd.ac.in [Department of Physics, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Gambhir, Vijayeta; Reddy, Martha N. [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India)

2015-08-31

In a typical Raman based sensor, a single laser beam is used for exciting the sample and the backscattered or forward scattered light is collected using collection optics and is analyzed by a spectrometer. We have investigated that by means of exciting the sample with multiple beams, i.e., by dividing the same input power of the single beam into two or three or more beams and exciting the sample from different angles, the Raman signal enhances significantly. Due to the presence of multiple beams passing through the same volume of the sample, an interference pattern is formed and the volume of interaction of excitation beams with the sample increases. By means of this geometry, the enhancement in the Raman signal is observed and it was found that the signal strength increases linearly with the increase in number of excitation beams. Experimental results of this scheme for excitation of the samples are reported for explosive detection at a standoff distance.

Compatible ecological niche signals between biological and archaeological datasets for late-surviving Neandertals.

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Bible, Rachael C; Peterson, A Townsend

2018-04-17

To assess ecological niche similarity for biological and archaeological samples representing late-surviving Neandertals in Europe to evaluate the validity of combining these two types of data in ecological niche modeling analyses. Tests of niche conservatism were used to assess niche similarity and niche identity of samples of morphologically diagnostic Neandertal remains and Middle Paleolithic (MP) archaeological sites dating to the time period leading up to Neandertal extinction. Paleoenvironmental reconstructions for the Pre-H4 (43.3-40.2 ky cal BP) were used as environmental space analyses. Null hypotheses of niche similarity and identity of the two types of samples could not be rejected. As primary and secondary evidence of Neandertal occurrence during the Pre-H4 show high levels of niche similarity and identity, combining the two types of occurrence data to create larger samples for niche analyses is justified without the concern that different environmental signals could complicate future research. © 2018 Wiley Periodicals, Inc.

Enhanced B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation contributes to ABCC1-mediated chemoresistance and glutathione-mediated survival in acquired topoisomerase II poison-resistant cancer cells.

Science.gov (United States)

Chen, Huang-Hui; Chang, Hsin-Huei; Chang, Jang-Yang; Tang, Ya-Chu; Cheng, Yung-Chi; Lin, Li-Mei; Cheng, Shu-Ying; Huang, Chih-Hsiang; Sun, Man-Wu; Chen, Chiung-Tong; Kuo, Ching-Chuan

2017-12-01

Nuclear factor erythroid-2-related factor 2 (NRF2) mainly regulates transcriptional activation through antioxidant-responsive elements (AREs) present in the promoters of NRF2 target genes. Recently, we found that NRF2 was overexpressed in a KB-derived drug-resistant cancer cell panel. In this panel, KB-7D cells, which show acquired resistance to topoisomerase II (Top II) poisons, exhibited the highest NRF2 activation. To investigate whether NRF2 directly contributed to acquired resistance against Top II poisons, we manipulated NRF2 by genetic and pharmacological approaches. The result demonstrated that silencing of NRF2 by RNA interference increased the sensitivity and treatment with NRF2 activator decreased the sensitivity of KB and KB-7D cells toward Top II poisons. Further, increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation activated NRF2 signaling in KB-7D cells. Moreover, increased binding of NRF2 to an ARE in the promoter of ATP-binding cassette subfamily C member 1 (ABCC1) directly contributed to Top II poison resistance. In addition, activation of NRF2 increased glutathione level and antioxidant capacity in KB-7D cells compared with that in KB cells; moreover, high glutathione level provided survival advantage to KB-7D cells. Our study is the first to show that aberrant NRF2 activation is via increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation, which increases the acquired resistance and promote the survival of Top II poison-resistant cancer cells. Importantly, NRF2 downstream effectors ABCC1 and glutathione directly contribute to acquired resistance and survival, respectively. These results suggest that blockade of NRF2 signaling may enhance therapeutic efficacy and reduce the survival of Top II poison-refractory tumors in clinical. Copyright © 2017 Elsevier Inc. All rights reserved.

A study on hybrid split-spectrum processing technique for enhanced reliability in ultrasonic signal analysis

International Nuclear Information System (INIS)

Huh, Hyung; Koo, Kil Mo; Cheong, Yong Moo; Kim, G. J.

1995-01-01

Many signal-processing techniques have been found to be useful in ultrasonic and nondestructive evaluation. Among the most popular techniques are signal averaging, spatial compounding, matched filters, and homomorphic processing. One of the significant new process is split-spectrum processing(SSP), which can be equally useful in signal-to-noise ratio(SNR) improvement and grain characterization in several engineering materials. The purpose of this paper is to explore the utility of SSP in ultrasonic NDE. A wide variety of engineering problems are reviewed and suggestions for implementation of the technique are provided. SSP uses the frequency-dependent response of the interfering coherent noise produced by unresolvable scatters in the resolution range cell of a transducer. It is implemented by splitting the Sequency spectrum of the received signal by using Gaussian bandpass filters. The theoretical basis for the potential of SSP for grain characterization in SUS 304 material is discussed, and some experimental-evidence for the feasibility of the approach is presented. Results of SNR enhancement in signals obtained from real four samples of SUS 304. The influence of various processing parameters on the performance of the processing technique is also discussed. The minimization algorithm. which provides an excellent SNR enhancement when used either in conjunction with other SSP algorithms like polarity-check or by itself, is also presented.

A Study on Hybrid Split-Spectrum Processing Technique for Enhanced Reliability in Ultrasonic Signal Analysis

International Nuclear Information System (INIS)

Huh, H.; Koo, K. M.; Kim, G. J.

1996-01-01

Many signal-processing techniques have been found to be useful in ultrasonic and nondestructive evaluation. Among the most popular techniques are signal averaging, spatial compounding, matched filters and homomorphic processing. One of the significant new process is split-spectrum processing(SSP), which can be equally useful in signal-to-noise ratio(SNR) improvement and grain characterization in several specimens. The purpose of this paper is to explore the utility of SSP in ultrasonic NDE. A wide variety of engineering problems are reviewed, and suggestions for implementation of the technique are provided. SSP uses the frequency-dependent response of the interfering coherent noise produced by unresolvable scatters in the resolution range cell of a transducer. It is implemented by splitting the frequency spectrum of the received signal by using gaussian bandpass filter. The theoretical basis for the potential of SSP for grain characterization in SUS 304 material is discussed, and some experimental evidence for the feasibility of the approach is presented. Results of SNR enhancement in signals obtained from real four samples of SUS 304. The influence of various processing parameters on the performance of the processing technique is also discussed. The minimization algorithm, which provides an excellent SNR enhancement when used either in conjunction with other SSP algorithms like polarity-check or by itself, is also presented

Signal enhancement due to high-Z nanofilm electrodes in parallel plate ionization chambers with variable microgaps.

Science.gov (United States)

Brivio, Davide; Sajo, Erno; Zygmanski, Piotr

2017-12-01

We developed a method for measuring signal enhancement produced by high-Z nanofilm electrodes in parallel plate ionization chambers with variable thickness microgaps. We used a laboratory-made variable gap parallel plate ionization chamber with nanofilm electrodes made of aluminum-aluminum (Al-Al) and aluminum-tantalum (Al-Ta). The electrodes were evaporated on 1 mm thick glass substrates. The interelectrode air gap was varied from 3 μm to 1 cm. The gap size was measured using a digital micrometer and it was confirmed by capacitance measurements. The electric field in the chamber was kept between 0.1 kV/cm and 1 kV/cm for all the gap sizes by applying appropriate compensating voltages. The chamber was exposed to 120 kVp X-rays. The current was measured using a commercial data acquisition system with temporal resolution of 600 Hz. In addition, radiation transport simulations were carried out to characterize the dose, D(x), high-energy electron current, J(x), and deposited charge, Q(x), as a function of distance, x, from the electrodes. A deterministic method was selected over Monte Carlo due to its ability to produce results with 10 nm spatial resolution without stochastic uncertainties. Experimental signal enhancement ratio, SER(G) which we defined as the ratio of signal for Al-air-Ta to signal for Al-air-Al for each gap size, was compared to computations. The individual contributions of dose, electron current, and charge deposition to the signal enhancement were determined. Experimental signals matched computed data for all gap sizes after accounting for several contributions to the signal: (a) charge carrier generated via ionization due to the energy deposited in the air gap, D(x); (b) high-energy electron current, J(x), leaking from high-Z electrode (Ta) toward low-Z electrode (Al); (c) deposited charge in the air gap, Q(x); and (d) the decreased collection efficiency for large gaps (>~500 μm). Q(x) accounts for the electrons below 100 eV, which are

Enhancement of the Signal-to-Noise Ratio in Sonic Logging Waveforms by Seismic Interferometry

KAUST Repository

Aldawood, Ali

2012-04-01

Sonic logs are essential tools for reliably identifying interval velocities which, in turn, are used in many seismic processes. One problem that arises, while logging, is irregularities due to washout zones along the borehole surfaces that scatters the transmitted energy and hence weakens the signal recorded at the receivers. To alleviate this problem, I have extended the theory of super-virtual refraction interferometry to enhance the signal-to-noise ratio (SNR) sonic waveforms. Tests on synthetic and real data show noticeable signal-to-noise ratio (SNR) enhancements of refracted P-wave arrivals in the sonic waveforms. The theory of super-virtual interferometric stacking is composed of two redatuming steps followed by a stacking procedure. The first redatuming procedure is of correlation type, where traces are correlated together to get virtual traces with the sources datumed to the refractor. The second datuming step is of convolution type, where traces are convolved together to dedatum the sources back to their original positions. The stacking procedure following each step enhances the signal to noise ratio of the refracted P-wave first arrivals. Datuming with correlation and convolution of traces introduces severe artifacts denoted as correlation artifacts in super-virtual data. To overcome this problem, I replace the datuming with correlation step by datuming with deconvolution. Although the former datuming method is more robust, the latter one reduces the artifacts significantly. Moreover, deconvolution can be a noise amplifier which is why a regularization term is utilized, rendering the datuming with deconvolution more stable. Tests of datuming with deconvolution instead of correlation with synthetic and real data examples show significant reduction of these artifacts. This is especially true when compared with the conventional way of applying the super-virtual refraction interferometry method.

Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

Science.gov (United States)

Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed; Li, Xiaoyan; Wu, Yaohong; Philpot, Benjamin D; Snider, William D; Newbern, Jason M

2016-01-01

Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability. DOI: http://dx.doi.org/10.7554/eLife.11123.001 PMID:26848828

Activation of CHK1 in Supporting Cells Indirectly Promotes Hair Cell Survival

Directory of Open Access Journals (Sweden)

Azadeh Jadali

2017-05-01

Full Text Available The sensory hair cells of the inner ear are exquisitely sensitive to ototoxic insults. Loss of hair cells after exposure to ototoxic agents causes hearing loss. Chemotherapeutic agents such as cisplatin causes hair cell loss. Cisplatin forms DNA mono-adducts as well as intra- and inter-strand DNA crosslinks. DNA cisplatin adducts are repaired through the DNA damage response. The decision between cell survival and cell death following DNA damage rests on factors that are involved in determining damage tolerance, cell survival and apoptosis. Cisplatin damage on hair cells has been the main focus of many ototoxic studies, yet the effect of cisplatin on supporting cells has been largely ignored. In this study, the effects of DNA damage response in cochlear supporting cells were interrogated. Supporting cells play a major role in the development, maintenance and oto-protection of hair cells. Loss of supporting cells may indirectly affect hair cell survival or maintenance. Activation of the Phosphoinositide 3-Kinase (PI3K signaling was previously shown to promote hair cell survival. To test whether activating PI3K signaling promotes supporting cell survival after cisplatin damage, cochlear explants from the neural subset (NS Cre Pten conditional knockout mice were employed. Deletion of Phosphatase and Tensin Homolog (PTEN activates PI3K signaling in multiple cell types within the cochlea. Supporting cells lacking PTEN showed increased cell survival after cisplatin damage. Supporting cells lacking PTEN also showed increased phosphorylation of Checkpoint Kinase 1 (CHK1 levels after cisplatin damage. Nearest neighbor analysis showed increased numbers of supporting cells with activated PI3K signaling in close proximity to surviving hair cells in cisplatin damaged cochleae. We propose that increased PI3K signaling promotes supporting cell survival through phosphorylation of CHK1 and increased survival of supporting cells indirectly increases hair cell

Enhancement of crack detection in stud bolts of nuclear reactor by ultrasonic signal processing technique

International Nuclear Information System (INIS)

Lee, J.H.; Oh, W.D.; Choi, S.W.; Park, M.H.

2004-01-01

'Full-text:' The stud bolts is one of the most critical parts for safety of reactor vessels in the nuclear power plants. However, in the application of ultrasonic technique for crack detection in stud bolt, some difficulties encountered are classification of crack signal from the signals reflected from threads part in stud bolt. In this study, shadow effect technique combined with new signal processing method is Investigated to enhance the detectability of small crack initiated from root of thread in stud bolt. The key idea of signal processing is based on the fact that the shape of waveforms from the threads is uniform since the shape of the threads in a bolt is same. If some cracks exist in the thread, the flaw signals are different to the reference signals. It is demonstrated that the small flaws are efficiently detected by novel ultrasonic technique combined with this new signal processing concept. (author)

Polarization-based enhancement of ocean color signal for estimating suspended particulate matter: radiative transfer simulations and laboratory measurements.

Science.gov (United States)

Liu, Jia; He, Xianqiang; Liu, Jiahang; Bai, Yan; Wang, Difeng; Chen, Tieqiao; Wang, Yihao; Zhu, Feng

2017-04-17

Absorption and scattering by molecules, aerosols and hydrosols, and the reflection and transmission over the sea surface can modify the original polarization state of sunlight. However, water-leaving radiance polarization, containing embedded water constituent information, has largely been neglected. Here, the efficiency of the parallel polarization radiance (PPR) for enhancing ocean color signal of suspended particulate matter is examined via vector radiative transfer simulations and laboratory experiments. The simulation results demonstrate that the PPR has a slightly higher ocean color signal at the top-of-atmosphere as compared with that of the total radiance. Moreover, both the simulations and laboratory measurements reveal that, compared with total radiance, PPR can effectively enhance the normalized ocean color signal for a large range of observation geometries, wavelengths, and suspended particle concentrations. Thus, PPR has great potential for improving the ocean color signal detection from satellite.

Exosomes confer pro-survival signals to alter the phenotype of prostate cells in their surrounding environment

Science.gov (United States)

Hosseini-Beheshti, Elham; Choi, Wendy; Weiswald, Louis-Bastien; Kharmate, Geetanjali; Ghaffari, Mazyar; Roshan-Moniri, Mani; Hassona, Mohamed D.; Chan, Leslie; Chin, Mei Yieng; Tai, Isabella T.; Rennie, Paul S.; Fazli, Ladan; Guns, Emma S. Tomlinson

2016-01-01

Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Current research on tumour-related extracellular vesicles (EVs) suggests that exosomes play a significant role in paracrine signaling pathways, thus potentially influencing cancer progression via multiple mechanisms. In fact, during the last decade numerous studies have revealed the role of EVs in the progression of various pathological conditions including cancer. Moreover, differences in the proteomic, lipidomic, and cholesterol content of exosomes derived from PCa cell lines versus benign prostate cell lines confirm that exosomes could be excellent biomarker candidates. As such, as part of an extensive proteomic analysis using LCMS we previously described a potential role of exosomes as biomarkers for PCa. Current evidence suggests that uptake of EV's into the local tumour microenvironment encouraging us to further examine the role of these vesicles in distinct mechanisms involved in the progression of PCa and castration resistant PCa. For the purpose of this study, we hypothesized that exosomes play a pivotal role in cell-cell communication in the local tumour microenvironment, conferring activation of numerous survival mechanisms during PCa progression and development of therapeutic resistance. Our in vitro results demonstrate that PCa derived exosomes significantly reduce apoptosis, increase cancer cell proliferation and induce cell migration in LNCaP and RWPE-1 cells. In conjunction with our in vitro findings, we have also demonstrated that exosomes increased tumor volume and serum PSA levels in vivo when xenograft bearing mice were administered DU145 cell derived exosomes intravenously. This research suggests that, regardless of androgen receptor phenotype, exosomes derived from PCa cells significantly enhance multiple mechanisms that contribute to PCa progression. PMID:26840259

Stress-triggered signaling affecting survival or suicide of Streptococcus pneumoniae.

Science.gov (United States)

Cortes, Paulo R; Piñas, Germán E; Cian, Melina B; Yandar, Nubia; Echenique, Jose

2015-01-01

Streptococcus pneumoniae is a major human pathogen that can survive to stress conditions, such as the acidic environment of inflammatory foci, and tolerates lethal pH through a mechanism known as the acid tolerance response. We previously described that S. pneumoniae activates acidic-stress induced lysis in response to acidified environments, favoring the release of cell wall compounds, DNA and virulence factors. Here, we demonstrate that F(0)F(1)-ATPase is involved in the response to acidic stress. Chemical inhibitors (DCCD, optochin) of this proton pump repressed the ATR induction, but caused an increased ASIL. Confirming these findings, mutants of the subunit c of this enzyme showed the same phenotypes as inhibitors. Importantly, we demonstrated that F(0)F(1)-ATPase and ATR are necessary for the intracellular survival of the pneumococcus in macrophages. Alternatively, a screening of two-component system (TCS) mutants showed that ATR and survival in pneumocytes were controlled in contrasting ways by ComDE and CiaRH, which had been involved in the ASIL mechanism. Briefly, CiaRH was essential for ATR (ComE represses activation) whereas ComE was necessary for ASIL (CiaRH protects against induction). They did not regulate F0F1-ATPase expression, but control LytA expression on the pneumococcal surface. These results suggest that both TCSs and F(0)F(1)-ATPase control a stress response and decide between a survival or a suicide mechanism by independent pathways, either in vitro or in pneumocyte cultures. This biological model contributes to the current knowledge about bacterial response under stress conditions in host tissues, where pathogens need to survive in order to establish infections. Copyright © 2014 Elsevier GmbH. All rights reserved.

Enhancing Brassinosteroid Signaling via Overexpression of Tomato (Solanum lycopersicum SlBRI1 Improves Major Agronomic Traits

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Shuming Nie

2017-08-01

Full Text Available Brassinosteroids (BRs play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1, which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato (Solanum lycopersicum BRI1 gene, SlBRI1, on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits.

Enhancement of survival of alginate-encapsulated Lactobacillus casei NCDC 298.

Science.gov (United States)

Mandal, Surajit; Hati, Subrota; Puniya, Anil Kumar; Khamrui, Kaushik; Singh, Kishan

2014-08-01

Micro-encapsulation of hydrocolloids improves the survival of sensitive probiotic bacteria in the harsh conditions that prevail in foods and during gastrointestinal passage by segregating them from environments. Incorporation of additives in encapsulating hydrocolloids and coatings of microcapsules further improves the survival of the probiotics. In this study, the effect of incorporation of resistant-maize starch in alginate for micro-encapsulation and coating of microcapsules with poly-l-lysine, stearic acid and bees wax on the survival of encapsulated Lactobacillus casei NCDC 298 at pH 1.5, 2% high bile salt, 65 °C for 20 min and release of viable lactobacilli cells from the capsule matrix in simulated aqueous solutions of colonic pH were assessed. Addition of resistant maize starch (2%) improved the survival of encapsulated L. casei NCDC 298. Coating of microcapsules with poly-L-lysine did not further improve the protection of encapsulated cells from the harsh conditions; however, bees wax and stearic acid (2%) improved the survival under similar conditions. Incorporation of maize starch (2%) in alginate followed by coating of beads with stearic acid (2%) led to better protection and complete release of entrapped lactobacilli in simulated colonic pH solution was observed. Additional treatments improve the survival of alginate-encapsulated lactobacilli cells without hindering the release of active cells from the capsule matrix and hence, the resulting encapsulated probiotics can be exploited in the development of probiotic functional foods with better survival of sensitive probiotic organisms. © 2013 Society of Chemical Industry.

Enhanced Schottky signals from electron-cooled, coasting beams in a heavy-ion storage ring

Energy Technology Data Exchange (ETDEWEB)

Krantz, C., E-mail: claude.krantz@mpi-hd.mpg.d [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); Blaum, K.; Grieser, M. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); Litvinov, Yu.A. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); GSI Helmholtzzentrum fuer Schwerionenforschung, Planckstrasse 1, D-64291 Darmstadt (Germany); Repnow, R.; Wolf, A. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany)

2011-02-11

Measurements at the Test Storage Ring of the Max-Planck-Institut fuer Kernphysik in Heidelberg (Germany) have shown that the signal amplitude induced in a Schottky-noise pickup electrode by a coasting electron-cooled ion beam can be greatly enhanced by exposure of the latter to a perturbing radiofrequency signal which is detuned from the true beam revolution frequency. The centre frequencies obtained from harmonic analysis of the observed pickup signal closely follow those imposed on the ions by the electron cooling force. The phenomenon can be exploited to measure the true revolution frequency of ion beams of very low intensity, whose pure Schottky noise is too weak to be measurable under normal circumstances.

Circadian regulation of hormone signaling and plant physiology.

Science.gov (United States)

Atamian, Hagop S; Harmer, Stacey L

2016-08-01

The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circadian clock and hormone signaling pathways.

B-Cell Activation and Tolerance Mediated by B-Cell Receptor, Toll-Like Receptor, and Survival Signal Crosstalk in SLE Pathogenesis

Science.gov (United States)

2017-09-01

Dec, 2016 "Integrating innate , adaptive, & survival signals to control B cell selection, homeostasis and tolerance" Pasteur Institute of Shanghai...secondary lymphoid tissues. Aging Dis. 2: 361–373. 8. Goenka, R., J. L. Scholz, M. S. Naradikian, and M. P. Cancro. 2014. Memory B cells form in aged...Scholz, and M. P. Cancro. 2011. A B- cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118: 1294–1304. 10. Rubtsov, A

Tyk2 expression and its signaling enhances the invasiveness of prostate cancer cells

International Nuclear Information System (INIS)

Ide, Hisamitsu; Nakagawa, Takashi; Terado, Yuichi; Kamiyama, Yutaka; Muto, Satoru; Horie, Shigeo

2008-01-01

Protein tyrosine kinase plays a central role in the proliferation and differentiation of various types of cells. One of these protein kinases, Tyk2, a member of the Jak family kinases, is known to play important roles in receptor signal transduction by interferons, interleukins, growth factors, and other hormones. In the present study, we investigated Tyk2 expression and its role in the growth and invasiveness of human prostate cancer cells. We used a small interfering RNA targeting Tyk2 and an inhibitor of Tyk2, tyrphostin A1, to suppress the expression and signaling of Tyk2 in prostate cancer cells. We detected mRNAs for Jak family kinases in prostate cancer cell lines by RT-PCR and Tyk2 protein in human prostate cancer specimens by immunohistochemistry. Inhibition of Tyk2 signaling resulted in attenuation of the urokinase-type plasminogen activator-enhanced invasiveness of prostate cancer cells in vitro without affecting the cellular growth rate. These results suggest that Tyk2 signaling in prostate cancer cells facilitate invasion of these cells, and interference with this signaling may be a potential therapeutic pathway

Double-labeled donor probe can enhance the signal of fluorescence resonance energy transfer (FRET) in detection of nucleic acid hybridization

Science.gov (United States)

Okamura, Yukio; Kondo, Satoshi; Sase, Ichiro; Suga, Takayuki; Mise, Kazuyuki; Furusawa, Iwao; Kawakami, Shigeki; Watanabe, Yuichiro

2000-01-01

A set of fluorescently-labeled DNA probes that hybridize with the target RNA and produce fluorescence resonance energy transfer (FRET) signals can be utilized for the detection of specific RNA. We have developed probe sets to detect and discriminate single-strand RNA molecules of plant viral genome, and sought a method to improve the FRET signals to handle in vivo applications. Consequently, we found that a double-labeled donor probe labeled with Bodipy dye yielded a remarkable increase in fluorescence intensity compared to a single-labeled donor probe used in an ordinary FRET. This double-labeled donor system can be easily applied to improve various FRET probes since the dependence upon sequence and label position in enhancement is not as strict. Furthermore this method could be applied to other nucleic acid substances, such as oligo RNA and phosphorothioate oligonucleotides (S-oligos) to enhance FRET signal. Although the double-labeled donor probes labeled with a variety of fluorophores had unexpected properties (strange UV-visible absorption spectra, decrease of intensity and decay of donor fluorescence) compared with single-labeled ones, they had no relation to FRET enhancement. This signal amplification mechanism cannot be explained simply based on our current results and knowledge of FRET. Yet it is possible to utilize this double-labeled donor system in various applications of FRET as a simple signal-enhancement method. PMID:11121494

Extinction ratio enhancement of SOA-based delayed-interference signal converter using detuned filtering

Science.gov (United States)

Zhang, B.; Kumar, S.; Yan, L.-S.; Willner, A. E.

2007-12-01

We demonstrate experimentally >3 dB extinction ratio improvement at the output of SOA-based delayed-interference signal converter (DISC) using optical off-centered filtering. Through careful modeling of the carrier and the phase dynamics, we explain in detail the origin of sub-pulses in the wavelength converted output, with an emphasis on the time-resolved frequency chirping of the output signal. Through our simulations we conclude that the sub-pulses and the main-pulses are oppositely chirped, which is also verified experimentally by analyzing the output with a chirp form analyzer. We propose and demonstrate an optical off-center filtering technique which effectively suppresses these sub-pulses. The effects of filter detuning and phase bias adjustment in the delayed-interferometer are experimentally characterized and optimized, leading to a >3 dB extinction ratio enhancement of the output signal.

Overexpression of FABP3 inhibits human bone marrow derived mesenchymal stem cell proliferation but enhances their survival in hypoxia

International Nuclear Information System (INIS)

Wang, Suna; Zhou, Yifu; Andreyev, Oleg; Hoyt, Robert F.; Singh, Avneesh; Hunt, Timothy; Horvath, Keith A.

2014-01-01

Studying the proliferative ability of human bone marrow derived mesenchymal stem cells in hypoxic conditions can help us achieve the effective regeneration of ischemic injured myocardium. Cardiac-type fatty acid binding protein (FABP3) is a specific biomarker of muscle and heart tissue injury. This protein is purported to be involved in early myocardial development, adult myocardial tissue repair and responsible for the modulation of cell growth and proliferation. We have investigated the role of FABP3 in human bone marrow derived mesenchymal stem cells under ischemic conditions. MSCs from 12 donors were cultured either in standard normoxic or modified hypoxic conditions, and the differential expression of FABP3 was tested by quantitative RT PCR and western blot. We also established stable FABP3 expression in MSCs and searched for variation in cellular proliferation and differentiation bioprocesses affected by hypoxic conditions. We identified: (1) the FABP3 differential expression pattern in the MSCs under hypoxic conditions; (2) over-expression of FABP3 inhibited the growth and proliferation of the MSCs; however, improved their survival in low oxygen environments; (3) the cell growth factors and positive cell cycle regulation genes, such as PCNA, APC, CCNB1, CCNB2 and CDC6 were all down-regulated; while the key negative cell cycle regulation genes TP53, BRCA1, CASP3 and CDKN1A were significantly up-regulated in the cells with FABP3 overexpression. Our data suggested that FABP3 was up-regulated under hypoxia; also negatively regulated the cell metabolic process and the mitotic cell cycle. Overexpression of FABP3 inhibited cell growth and proliferation via negative regulation of the cell cycle and down-regulation of cell growth factors, but enhances cell survival in hypoxic or ischemic conditions. - Highlights: • FABP3 expression pattern was studied in 12 human hypoxic-MSCs. • FABP3 mRNA and proteins are upregulated in the MSCs under hypoxic conditions. �

Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

Energy Technology Data Exchange (ETDEWEB)

Matoori, Simon [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Froehlich, Johannes M. [Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zurich (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Breitenstein, Stefan [Cantonal Hospital Winterthur, Department of Surgery, Clinic for Visceral and Thoracic Surgery, Winterthur (Switzerland); Doert, Aleksis [Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Pozdniakova, Viktoria [Stavanger University Hospital, Department of Radiology, Stavanger (Norway); Koh, Dow-Mu [Royal Marsden Hospital, Department of Radiology, Surrey, England (United Kingdom); Gutzeit, Andreas [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland)

2016-06-15

To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

International Nuclear Information System (INIS)

Matoori, Simon; Froehlich, Johannes M.; Breitenstein, Stefan; Doert, Aleksis; Pozdniakova, Viktoria; Koh, Dow-Mu; Gutzeit, Andreas

2016-01-01

To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

In vivo bioluminescence imaging for prolonged survival of transplanted human neural stem cells using 3D biocompatible scaffold in corticectomized rat model.

Directory of Open Access Journals (Sweden)

Do Won Hwang

Full Text Available Stem cell-based treatment of traumatic brain injury has been limited in its capacity to bring about complete functional recovery, because of the poor survival rate of the implanted stem cells. It is known that biocompatible biomaterials play a critical role in enhancing survival and proliferation of transplanted stem cells via provision of mechanical support. In this study, we noninvasively monitored in vivo behavior of implanted neural stem cells embedded within poly-l-lactic acid (PLLA scaffold, and showed that they survived over prolonged periods in corticectomized rat model. Corticectomized rat models were established by motor-cortex ablation of the rat. F3 cells expressing enhanced firefly luciferase (F3-effLuc were established through retroviral infection. The F3-effLuc within PLLA was monitored using IVIS-100 imaging system 7 days after corticectomized surgery. F3-effLuc within PLLA robustly adhered, and gradually increased luciferase signals of F3-effLuc within PLLA were detected in a day dependent manner. The implantation of F3-effLuc cells/PLLA complex into corticectomized rats showed longer-lasting luciferase activity than F3-effLuc cells alone. The bioluminescence signals from the PLLA-encapsulated cells were maintained for 14 days, compared with 8 days for the non-encapsulated cells. Immunostaining results revealed expression of the early neuronal marker, Tuj-1, in PLLA-F3-effLuc cells in the motor-cortex-ablated area. We observed noninvasively that the mechanical support by PLLA scaffold increased the survival of implanted neural stem cells in the corticectomized rat. The image-guided approach easily proved that scaffolds could provide supportive effect to implanted cells, increasing their viability in terms of enhancing therapeutic efficacy of stem-cell therapy.

Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

Science.gov (United States)

Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

2016-04-01

Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

The Spalt transcription factors regulate cell proliferation, survival and epithelial integrity downstream of the Decapentaplegic signalling pathway

Directory of Open Access Journals (Sweden)

María F. Organista

2012-10-01

The expression of the spalt genes is regulated by the Decapentaplegic signalling pathway in the Drosophila wing. These genes participate in the patterning of the longitudinal wing veins by regulating the expression of vein-specific genes, and in the establishment of cellular affinities in the central region of the wing blade epithelium. The Spalt proteins act as transcription factors, most likely regulating gene expression by repression, but the identity of their target genes in the wing is still unknown. As a preliminary step to unravel the genetic hierarchy controlled by the Spalt proteins, we have analysed their requirements during wing development, and addressed to what extent they mediate all the functions of the Decapentaplegic pathway in this developmental system. We identify additional functions for Spalt in cell division, survival, and maintenance of epithelial integrity. Thus, Spalt activity is required to promote cell proliferation, acting in the G2/M transition of the cell cycle. The contribution of Spalt to cell division is limited to the central region of the wing blade, as they do not mediate the extra growth triggered by Decapentaplegic signalling in the peripheral regions of the wing disc. In addition, Spalt function is required to maintain cell viability in cells exposed to high levels of Decapentaplegic signalling. This aspect of Spalt function is related to the repression of JNK signalling in the spalt domain of expression. Finally, we further characterise the requirements of Spalt to maintain epithelial integrity by regulating cellular affinities between cells located in the central wing region. Our results indicate that Spalt function mediates most of the requirements identified for Decapentaplegic signalling, contributing to establish the cellular qualities that differentiate central versus peripheral territories in the wing blade.

Human umbilical-cord-blood mononucleated cells enhance the survival of lethally irradiated mice. Dosage and the window of time

International Nuclear Information System (INIS)

Kovalenko, Olga A.; Ende, Norman; Azzam, Edouard I.

2013-01-01

The purpose of this study was to evaluate the window of time and dose of human umbilical-cord-blood (HUCB) mononucleated cells necessary for successful treatment of radiation injury in mice. Female A/J mice (27-30 weeks old) were exposed to an absorbed dose of 9-10 Gy of 137 Cs γ-rays delivered acutely to the whole body. They were treated either with 1 × 10 8 or 2 × 10 8 HUCB mononucleated cells at 24-52 h after the irradiation. The antibiotic Levaquin was applied 4 h postirradiation. The increased dose of cord-blood cells resulted in enhanced survival. The enhancement of survival in animals that received 2 × 10 8 HUCB mononucleated cells relative to irradiated but untreated animals was highly significant (P < 0.01). Compared with earlier studies, the increased dose of HUCB mononucleated cells, coupled with early use of an antibiotic, extended the window of time for effective treatment of severe radiation injury from 4 to 24-52 h after exposure. (author)

Neuronal survival in the brain: neuron type-specific mechanisms

DEFF Research Database (Denmark)

Pfisterer, Ulrich Gottfried; Khodosevich, Konstantin

2017-01-01

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial...... numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether...... for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various...

Reflexive Aero Structures for Enhanced Survivability, Phase I

Data.gov (United States)

National Aeronautics and Space Administration — Cornerstone Research Group Inc. (CRG) proposes to develop an advanced reflexive structure system to increase the survivability of aerostructures. This reflexive...

On enhancing drugs effect on radiosensitivity of HeLa cells by inhibiting P13K/Akt signal transduction

International Nuclear Information System (INIS)

Xia Shu; Yu Shiying

2006-01-01

Objective: To explore the mechanism of PI3K/Akt in radiosensitization of docetaxel and cisplatin by inhibiting PI3K/Akt pathway in HeLa cells. Methods: To detect the 50% inhibition concentration (IC 50 ) of cisplatin and docetaxel in Hela cells by mono-nuclear cell direct cytotoxicity assay (MTT) in vitro. Using the IC 20 of cisplatin and docetaxel in Hela cell or in association with LY294002 for 24 h, then, the cells were irradiated by X-ray with 2,3,4,6,8 Gy. The cell survival fraction was computed by clone formation. Cell survival curve was fitted by multitarget one-hit model, and D q , D 0 , SF 2 , sensitizing enhancing ratio(SER) was calculated. The expression of pAkt and total Akt by western blot were detected. Apoptosis was detected by flow cytometry. Results: 1. Docetaxel and cisplatin improved the phosphorylation of Akt by irradiation obviously. 2. The SER of docetaxel + LY294002 + irradiation group (1.92) was higher than that of docetaxel + irradiation group(1.41). The SER of cisplatin + LY294002 + irradiation group(1.71) was higher than the cisplatin + irradiation group (1.37). 3. Apoptosis rate of docetaxel + LY294002 + irradiation and cisplatin + LY294002 + irradiation groups(12.5%, 10.2%) were higher than those of docetaxel + irradiation and cisplatin + irradiation groups(6.1%, 5.1%). Conclusions: PI3K/Akt signal transduction activation may be as an important reason of radiosensitization reduction of docetaxel and cisplatin in the HeLa cells. Our results show that inhibiting PI3K/Akt can improve the radiosensitization of docetaxel and cisplatin in the HeLa cells. (authors)

IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival.

Science.gov (United States)

Webster, K E; Kim, H-O; Kyparissoudis, K; Corpuz, T M; Pinget, G V; Uldrich, A P; Brink, R; Belz, G T; Cho, J-H; Godfrey, D I; Sprent, J

2014-09-01

Natural killer T (NKT) cells are innate-like T cells that rapidly recognize pathogens and produce cytokines that shape the ensuing immune response. IL-17-producing NKT cells are enriched in barrier tissues, such as the lung, skin, and peripheral lymph nodes, and the factors that maintain this population in the periphery have not been elucidated. Here we show that NKT17 cells deviate from other NKT cells in their survival requirements. In contrast to conventional NKT cells that are maintained by IL-15, RORγt(+) NKT cells are IL-15 independent and instead rely completely on IL-7. IL-7 initiates a T-cell receptor-independent (TCR-independent) expansion of NKT17 cells, thus supporting their homeostasis. Without IL-7, survival is dramatically impaired, yet residual cells remain lineage committed with no downregulation of RORγt evident. Their preferential response to IL-7 does not reflect enhanced signaling through STAT proteins, but instead is modulated via the PI3K/AKT/mTOR signaling pathway. The ability to compete for IL-7 is dependent on high-density IL-7 receptor expression, which would promote uptake of low levels of IL-7 produced in the non-lymphoid sites of lung and skin. This dependence on IL-7 is also reported for RORγt(+) innate lymphoid cells and CD4(+) Th17 cells, and suggests common survival requirements for functionally similar cells.

Real-time implementations of acoustic signal enhancement techniques for aerial based surveillance and rescue applications

Science.gov (United States)

Ramos, Antonio L. L.; Shao, Zhili; Holthe, Aleksander; Sandli, Mathias F.

2017-05-01

The introduction of the System-on-Chip (SoC) technology has brought exciting new opportunities for the development of smart low cost embedded systems spanning a wide range of applications. Currently available SoC devices are capable of performing high speed digital signal processing tasks in software while featuring relatively low development costs and reduced time-to-market. Unmanned aerial vehicles (UAV) are an application example that has shown tremendous potential in an increasing number of scenarios, ranging from leisure to surveillance as well as in search and rescue missions. Video capturing from UAV platforms is a relatively straightforward task that requires almost no preprocessing. However, that does not apply to audio signals, especially in cases where the data is to be used to support real-time decision making. In fact, the enormous amount of acoustic interference from the surroundings, including the noise from the UAVs propellers, becomes a huge problem. This paper discusses a real-time implementation of the NLMS adaptive filtering algorithm applied to enhancing acoustic signals captured from UAV platforms. The model relies on a combination of acoustic sensors and a computational inexpensive algorithm running on a digital signal processor. Given its simplicity, this solution can be incorporated into the main processing system of an UAV using the SoC technology, and run concurrently with other required tasks, such as flight control and communications. Simulations and real-time DSP-based implementations have shown significant signal enhancement results by efficiently mitigating the interference from the noise generated by the UAVs propellers as well as from other external noise sources.

Survival of hypoxic human mesenchymal stem cells is enhanced by a positive feedback loop involving miR-210 and hypoxia-inducible factor 1.

Science.gov (United States)

Chang, Woochul; Lee, Chang Youn; Park, Jun-Hee; Park, Moon-Seo; Maeng, Lee-So; Yoon, Chee Soon; Lee, Min Young; Hwang, Ki-Chul; Chung, Yong-An

2013-01-01

The use of mesenchymal stem cells (MSCs) has emerged as a potential new treatment for myocardial infarction. However, the poor viability of MSCs after transplantation critically limits the efficacy of this new strategy. The expression of microRNA-210 (miR-210) is induced by hypoxia and is important for cell survival under hypoxic conditions. Hypoxia increases the levels of hypoxia inducible factor-1 (HIF-1) protein and miR-210 in human MSCs (hMSCs). miR-210 positively regulates HIF-1α activity. Furthermore, miR-210 expression is also induced by hypoxia through the regulation of HIF-1α. To investigate the effect of miR-210 on hMSC survival under hypoxic conditions, survival rates along with signaling related to cell survival were evaluated in hMSCs over-expressing miR-210 or ones that lacked HIF-1α expression. Elevated miR-210 expression increased survival rates along with Akt and ERK activity in hMSCs with hypoxia. These data demonstrated that a positive feedback loop involving miR-210 and HIF-1α was important for MSC survival under hypoxic conditions.

Development of rations for the enhanced survival of salmon

International Nuclear Information System (INIS)

Ewing, R.D.; Lagasse, J.P.

1990-12-01

The nutritional quality of feed plays an important role in determining the health and ''fitness'' of smolts. Commercial fish meal, the major source of protein in salmon rations, may be reduced in quality from poor drying techniques during manufacture. Dietary stress in the hatchery may result. This investigation tests the hypothesis that protein quality of fish rations can influence the survival of smolts and the ultimate return of adults. The test involves a comparison between performances of coho (Oncorhynchus kisutch) and chinook salmon (O. tshawytscha) reared on rations containing very high quality protein derived from vacuum dried meals and those of fish reared on commercial rations, with commercial fish meal as a source of protein. Survival and return of several brood years of test and control fish are used to measure the influence of ration on survival. This report includes recovery data from these marked fish collected 1982 through September 1990

Reflexive Aero Structures for Enhanced Survivability, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — Cornerstone Research Group Inc. (CRG) will develop an advanced reflexive structure technology system to increase the survivability of future systems constructed of...

PTP1B Inhibition Causes Rac1 Activation by Enhancing Receptor Tyrosine Kinase Signaling

Directory of Open Access Journals (Sweden)

Ayako Tsuchiya

2014-04-01

Full Text Available Background/Aims: The present study investigated the signaling pathway underlying Rac1 activation induced by the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl-cyclopropyl]-octanoic acid (DCP-LA. Methods: Activity of protein tyrosine phosphatase 1B (PTP1B was assayed under cell-free conditions. Western blot was carried out to quantify phosphorylation of insulin receptor substrate-1 (IRS-1 and Akt in PC-12 cells. Rac1 activity was monitored in the föerster resonance energy transfer (FRET analysis using living and fixed PC-12 cells. Results: DCP-LA markedly suppressed PTP1B activity in a concentration (100 pM-100 µM-dependent manner. In the DCP-LA binding assay, fluorescein-conjugated DCP-LA produced a single fluorescent signal band at 60 kDa, corresponding to the molecule of PTP1B, and the signal was attenuated or abolished by co-treatment or pretreatment with non-conjugated DCP-LA. DCP-LA significantly enhanced nerve growth factor (NGF-stimulated phosphorylation of IRS-1 at Tyr1222 and Akt1/2 at Thr308/309 and Ser473/474 in PC-12 cells. In the FRET analysis, DCP-LA significantly enhanced NGF-stimulated Rac1 activation, which is abrogated by the phosphatidylinositol 3 kinase (PI3K inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase-1 (PDK1 inhibitor BX912, or the Akt inhibitor MK2206. Conclusion: The results of the present study show that DCP-LA-induced PTP1B inhibition, possibly through its direct binding, causes Rac1 activation by enhancing a pathway along a receptor tyrosine kinase (RTK/IRS-1/PI3K/Akt/Rac1 axis.

Thioredoxin-1 promotes survival in cells exposed to S-nitrosoglutathione: Correlation with reduction of intracellular levels of nitrosothiols and up-regulation of the ERK1/2 MAP Kinases

International Nuclear Information System (INIS)

Arai, Roberto J.; Ogata, Fernando T.; Batista, Wagner L.; Masutani, Hiroshi; Yodoi, Junji; Debbas, Victor; Augusto, Ohara; Stern, Arnold; Monteiro, Hugo P.

2008-01-01

Accumulating evidence indicates that post-translational protein modifications by nitric oxide and its derived species are critical effectors of redox signaling in cells. These protein modifications are most likely controlled by intracellular reductants. Among them, the importance of the 12 kDa dithiol protein thioredoxin-1 (TRX-1) has been increasingly recognized. However, the effects of TRX-1 in cells exposed to exogenous nitrosothiols remain little understood. We investigated the levels of intracellular nitrosothiols and survival signaling in HeLa cells over-expressing TRX-1 and exposed to S-nitrosoglutahione (GSNO). A role for TRX-1 expression on GSNO catabolism and cell viability was demonstrated by the concentration-dependent effects of GSNO on decreasing TRX-1 expression, activation of caspase-3, and increasing cell death. The over-expression of TRX-1 in HeLa cells partially attenuated caspase-3 activation and enhanced cell viability upon GSNO treatment. This was correlated with reduction of intracellular levels of nitrosothiols and increasing levels of nitrite and nitrotyrosine. The involvement of ERK, p38 and JNK pathways were investigated in parental cells treated with GSNO. Activation of ERK1/2 MAP kinases was shown to be critical for survival signaling. In cells over-expressing TRX-1, basal phosphorylation levels of ERK1/2 MAP kinases were higher and further increased after GSNO treatment. These results indicate that the enhanced cell viability promoted by TRX-1 correlates with its capacity to regulate the levels of intracellular nitrosothiols and to up-regulate the survival signaling pathway mediated by the ERK1/2 MAP kinases

Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling.

Directory of Open Access Journals (Sweden)

Md Shamim Hossain

Full Text Available The special glycerophospholipids plasmalogens (Pls are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh-RNA lentiviral particles revealed that the Pls-mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system.

Fission Yeast SCYL1/2 Homologue Ppk32: A Novel Regulator of TOR Signalling That Governs Survival during Brefeldin A Induced Stress to Protein Trafficking.

Science.gov (United States)

Kowalczyk, Katarzyna M; Petersen, Janni

2016-05-01

Target of Rapamycin (TOR) signalling allows eukaryotic cells to adjust cell growth in response to changes in their nutritional and environmental context. The two distinct TOR complexes (TORC1/2) localise to the cell's internal membrane compartments; the endoplasmic reticulum (ER), Golgi apparatus and lysosomes/vacuoles. Here, we show that Ppk32, a SCYL family pseudo-kinase, is a novel regulator of TOR signalling. The absence of ppk32 expression confers resistance to TOR inhibition. Ppk32 inhibition of TORC1 is critical for cell survival following Brefeldin A (BFA) induced stress. Treatment of wild type cells with either the TORC1 specific inhibitor rapamycin or the general TOR inhibitor Torin1 confirmed that a reduction in TORC1 activity promoted recovery from BFA induced stress. Phosphorylation of Ppk32 on two residues that are conserved within the SCYL pseudo-kinase family are required for this TOR inhibition. Phosphorylation on these sites controls Ppk32 protein levels and sensitivity to BFA. BFA induced ER stress does not account for the response to BFA that we report here, however BFA is also known to induce Golgi stress and impair traffic to lysosomes. In summary, Ppk32 reduce TOR signalling in response to BFA induced stress to support cell survival.

Human T-lymphotropic virus type-1 p30 alters cell cycle G2 regulation of T lymphocytes to enhance cell survival

Directory of Open Access Journals (Sweden)

Silverman Lee

2007-07-01

Full Text Available Abstract Background Human T-lymphotropic virus type-1 (HTLV-1 causes adult T-cell leukemia/lymphoma and is linked to a number of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13 and p30, whose roles are still being defined in the virus life cycle and in HTLV-1 virus-host cell interactions. Proviral clones of HTLV-1 with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. p30 expressed exogenously differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and while acting as a repressor of many genes including Tax, in part by blocking tax/rex RNA nuclear export, selectively enhances key gene pathways involved in T-cell signaling/activation. Results Herein, we analyzed the role of p30 in cell cycle regulation. Jurkat T-cells transduced with a p30 expressing lentivirus vector accumulated in the G2-M phase of cell cycle. We then analyzed key proteins involved in G2-M checkpoint activation. p30 expression in Jurkat T-cells resulted in an increase in phosphorylation at serine 216 of nuclear cell division cycle 25C (Cdc25C, had enhanced checkpoint kinase 1 (Chk1 serine 345 phosphorylation, reduced expression of polo-like kinase 1 (PLK1, diminished phosphorylation of PLK1 at tyrosine 210 and reduced phosphorylation of Cdc25C at serine 198. Finally, primary human lymphocyte derived cell lines immortalized by a HTLV-1 proviral clone defective in p30 expression were more susceptible to camptothecin induced apoptosis. Collectively these data are consistent with a cell survival role of p30 against genotoxic insults to HTLV-1 infected lymphocytes. Conclusion Collectively, our data are the first to indicate that HTLV-1 p30 expression results in activation of the G2-M cell cycle checkpoint, events that would promote early viral spread and T

Canonical Wnt signaling transiently stimulates proliferation and enhances neurogenesis in neonatal neural progenitor cultures

International Nuclear Information System (INIS)

Hirsch, Cordula; Campano, Louise M.; Woehrle, Simon; Hecht, Andreas

2007-01-01

Canonical Wnt signaling triggers the formation of heterodimeric transcription factor complexes consisting of β-catenin and T cell factors, and thereby controls the execution of specific genetic programs. During the expansion and neurogenic phases of embryonic neural development canonical Wnt signaling initially controls proliferation of neural progenitor cells, and later neuronal differentiation. Whether Wnt growth factors affect neural progenitor cells postnatally is not known. Therefore, we have analyzed the impact of Wnt signaling on neural progenitors isolated from cerebral cortices of newborn mice. Expression profiling of pathway components revealed that these cells are fully equipped to respond to Wnt signals. However, Wnt pathway activation affected only a subset of neonatal progenitors and elicited a limited increase in proliferation and neuronal differentiation in distinct subsets of cells. Moreover, Wnt pathway activation only transiently stimulated S-phase entry but did not support long-term proliferation of progenitor cultures. The dampened nature of the Wnt response correlates with the predominant expression of inhibitory pathway components and the rapid actuation of negative feedback mechanisms. Interestingly, in differentiating cell cultures activation of canonical Wnt signaling reduced Hes1 and Hes5 expression suggesting that during postnatal neural development, Wnt/β-catenin signaling enhances neurogenesis from progenitor cells by interfering with Notch pathway activity

Igf1r signaling is indispensable for preimplantation development and is activated via a novel function of E-cadherin.

Directory of Open Access Journals (Sweden)

Ivan Bedzhov

Full Text Available Insulin-like growth factor I receptor (Igf1r signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.

Fractal properties of background noise and target signal enhancement using CSEM data

Science.gov (United States)

Benavides, Alfonso; Everett, Mark E.; Pierce, Carl; Nguyen, Cam

2003-09-01

Controlled-source electromagnetic (CSEM) spatial profiles and 2-D conductivity maps were obtained on the Brazos Valley, TX floodplain to study the fractal statistics of geological signals and effects of man-made conductive targets using Geonics EM34, EM31 and EM63. Using target-free areas, a consistent power-law power spectrum (|A(k)| ~ k ^-β) for the profiles was found with β values typical of fractional Brownian motion (fBm). This means that the spatial variation of conductivity does not correspond to Gaussian statistics, where there are spatial correlations at different scales. The presence of targets tends to flatten the power-law power spectrum (PS) at small wavenumbers. Detection and localization of targets can be achieved using short-time Fourier transform (STFT). The presence of targets is enhanced because the signal energy is spread to higher wavenumbers (small scale numbers) in the positions occupied by the targets. In the case of poor spatial sampling or small amount of data, the information available from the power spectrum is not enough to separate spatial correlations from target signatures. Advantages are gained by using the spatial correlations of the fBm in order to reject the background response, and to enhance the signals from highly conductive targets. This approach was tested for the EM31 using a pre-processing step that combines apparent conductivity readings from two perpendicular transmitter-receiver orientations at each station. The response obtained using time-domain CSEM is influence to a lesser degree by geological noise and the target response can be processed to recover target features. The homotopy method is proposed to solve the inverse problem using a set of possible target models and a dynamic library of responses used to optimize the starting model.

Human engineering design considerations for the use of signal color enhancement in ASW displays

Energy Technology Data Exchange (ETDEWEB)

Banks, W.W.

1990-11-01

The Lawrence Livermore National Laboratory (LLNL) was requested to examine and define man-machine limits as part of the Office of Naval Technology's High Gain Initiative program (HGI). As an initial investigative area, LLNL's Systems and Human Performance effort focused upon color display interfaces and the use of color enhancement techniques to define human and system interface limits in signal detection and discrimination tasks. The knowledgeable and prudent use of color in different types of display is believed to facilitate human visual detection, discrimination and recognition in complex visual tasks. The consideration and understanding of the complex set of interacting variables associated with the prudent use of color is essential to optimize human performance, especially in the ASW community. The designers of advanced display technology and signal processing algorithms may be eventually called upon to present pre-processed information to ASW operators and researchers using the latest color enhancement techniques. These techniques, however, may be limited if one does not understand the complexity and limits of human information processing which reflects the assessed state of knowledge relevant to the use of color in displays. The initial sections of this report discuss various aspects of color presentation and the problems typically encountered, while the last section deals with a specific research proposal required to further our understanding and proper use of color enhancement methods.

Using hyperentanglement to enhance resolution, signal-to-noise ratio, and measurement time

Science.gov (United States)

Smith, James F.

2017-03-01

A hyperentanglement-based atmospheric imaging/detection system involving only a signal and an ancilla photon will be considered for optical and infrared frequencies. Only the signal photon will propagate in the atmosphere and its loss will be classical. The ancilla photon will remain within the sensor experiencing low loss. Closed form expressions for the wave function, normalization, density operator, reduced density operator, symmetrized logarithmic derivative, quantum Fisher information, quantum Cramer-Rao lower bound, coincidence probabilities, probability of detection, probability of false alarm, probability of error after M measurements, signal-to-noise ratio, quantum Chernoff bound, time-on-target expressions related to probability of error, and resolution will be provided. The effect of noise in every mode will be included as well as loss. The system will provide the basic design for an imaging/detection system functioning at optical or infrared frequencies that offers better than classical angular and range resolution. Optimization for enhanced resolution will be included. The signal-to-noise ratio will be increased by a factor equal to the number of modes employed during the hyperentanglement process. Likewise, the measurement time can be reduced by the same factor. The hyperentanglement generator will typically make use of entanglement in polarization, energy-time, orbital angular momentum and so on. Mathematical results will be provided describing the system's performance as a function of loss mechanisms and noise.

The Caenorhabditis elegans nicotinamidase PNC-1 enhances survival.

Science.gov (United States)

van der Horst, Armando; Schavemaker, Jolanda M; Pellis-van Berkel, Wendy; Burgering, Boudewijn M T

2007-04-01

In yeast, increasing the copy number of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sir2 extends lifespan, which can be inhibited by nicotinamide (Nam), the end-product of Sir2-mediated NAD-breakdown. Furthermore, the yeast pyrazinamidase/nicotinamidase PNC-1 can extend yeast lifespan by converting Nam. In Caenorhabditis elegans (C. elegans), increased dosage of the gene encoding SIR-2.1 also increases lifespan. Here, we report that knockdown of the C. elegans homologue of yeast PNC-1 as well as growing worms on Nam-containing medium significantly decreases adult lifespan. Accordingly, increased gene dosage of pnc-1 increases adult survival under conditions of oxidative stress. These data show for the first time the involvement of PNC-1/Nam in the survival of a multicellular organism and may also contribute to our understanding of lifespan regulation in mammals.

A Class of Optimal Rectangular Filtering Matrices for Single-Channel Signal Enhancement in the Time Domain

DEFF Research Database (Denmark)

Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

2013-01-01

In this paper, we introduce a new class of op- timal rectangular filtering matrices for single-channel speech enhancement. The new class of filters exploits the fact that the dimension of the signal subspace is lower than that of the full space. By doing this, extra degrees of freedom...... in the filters, that are otherwise reserved for preserving the signal subspace, can be used for achieving an improved output signal-to-noise ratio (SNR). Moreover, the filters allow for explicit control of the tradeoff between noise reduction and speech distortion via the chosen rank of the signal subspace...... and real signals. The results show a number of interesting things. Firstly, they show how speech distortion can be traded for noise reduction and vice versa in a seamless manner. Moreover, the introduced filter designs are capable of achieving both the upper and lower bounds for the output SNR via...

Hardware-efficient signal generation of layered/enhanced ACO-OFDM for short-haul fiber-optic links.

Science.gov (United States)

Wang, Qibing; Song, Binhuang; Corcoran, Bill; Boland, David; Zhu, Chen; Zhuang, Leimeng; Lowery, Arthur J

2017-06-12

Layered/enhanced ACO-OFDM is a promising candidate for intensity modulation and direct-detection based short-haul fiber-optic links due to its both power and spectral efficiency. In this paper, we firstly demonstrate a hardware-efficient real-time 9.375 Gb/s QPSK-encoded layered/enhanced asymmetrical clipped optical OFDM (L/E-ACO-OFDM) transmitter using a Virtex-6 FPGA. This L/E-ACO-OFDM signal is successfully transmitted over 20-km uncompensated standard single-mode fiber (S-SMF) using a directly modulated laser. Several methods are explored to reduce the FPGA's logic resource utilization by taking advantage of the L/E-ACO-OFDM's signal characteristics. We show that the logic resource occupation of L/E-ACO-OFDM transmitter is almost the same as that of DC-biased OFDM transmitter when they achieve the same spectral efficiency, proving its great potential to be used in a real-time short-haul optical transmission link.

Enhancement of the conductivity detection signal in capillary electrophoresis systems using neutral cyclodextrins as sweeping agents.

Science.gov (United States)

Boublík, Milan; Riesová, Martina; Dubský, Pavel; Gaš, Bohuslav

2018-06-01

Conductivity detection is a universal detection technique often encountered in electrophoretic separation systems, especially in modern chip-electrophoresis based devices. On the other hand, it is sparsely combined with another contemporary trend of enhancing limits of detection by means of various preconcentration strategies. This can be attributed to the fact that a preconcentration experimental setup usually brings about disturbances in a conductivity baseline. Sweeping with a neutral sweeping agent seems a good candidate for overcoming this problem. A neutral sweeping agent does not hinder the conductivity detection while a charged analyte may preconcentrate on its boundary due to a decrease in its effective mobility. This study investigates such sweeping systems theoretically, by means of computer simulations, and experimentally. A formula is provided for the reliable estimation of the preconcentration factor. Additionally, it is demonstrated that the conductivity signal can significantly benefit from slowing down the analyte and thus the overall signal enhancement can easily overweight amplification caused solely by the sweeping process. The overall enhancement factor can be deduced a priori from the linearized theory of electrophoresis implemented in the PeakMaster freeware. Sweeping by neutral cyclodextrin is demonstrated on an amplification of a conductivity signal of flurbiprofen in a real drug sample. Finally, a possible formation of unexpected system peaks in systems with a neutral sweeping agent is revealed by the computer simulation and confirmed experimentally. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simvastatin enhances bone morphogenetic protein receptor type II expression

International Nuclear Information System (INIS)

Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N.

2006-01-01

Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function

Solid-State NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization

International Nuclear Information System (INIS)

Takahashi, Hiroki; Bardet, Michel; De Paepe, Gael; Hediger, Sabine; Ayala, Isabel; Simorre, Jean-Pierre

2013-01-01

Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool. (authors)

Solid-state NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization.

Science.gov (United States)

Takahashi, Hiroki; Ayala, Isabel; Bardet, Michel; De Paëpe, Gaël; Simorre, Jean-Pierre; Hediger, Sabine

2013-04-03

Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool.

H2O2 attenuates IGF-1R tyrosine phosphorylation and its survival signaling properties in neuronal cells via NR2B containing NMDA receptor.

Science.gov (United States)

Zeng, Zhiwen; Wang, Dejun; Gaur, Uma; Rifang, Liao; Wang, Haitao; Zheng, Wenhua

2017-09-12

Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H 2 O 2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H 2 O 2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H 2 O 2 , whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca 2+ influx contributes to the effects of H 2 O 2 . Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H 2 O 2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca 2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.

Errantum: Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins

Directory of Open Access Journals (Sweden)

Lai JCK

2010-12-01

Full Text Available Lai JCK, Ananthakrishnan G, Jandhyam S, et al. Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins. Int J Nanomedicine. 2010;5:715–723.The wrong image was used in Figure 5 on page 719.

REST/NRSF Knockdown Alters Survival, Lineage Differentiation and Signaling in Human Embryonic Stem Cells.

Directory of Open Access Journals (Sweden)

Kaushali Thakore-Shah

Full Text Available REST (RE1 silencing transcription factor, also known as NRSF (neuron-restrictive silencer factor, is a well-known transcriptional repressor of neural genes in non-neural tissues and stem cells. Dysregulation of REST activity is thought to play a role in diverse diseases including epilepsy, cancer, Down's syndrome and Huntington's disease. The role of REST/NRSF in control of human embryonic stem cell (hESC fate has never been examined. To evaluate the role of REST in hESCs we developed an inducible REST knockdown system and examined both growth and differentiation over short and long term culture. Interestingly, we have found that altering REST levels in multiple hESC lines does not result in loss of self-renewal but instead leads to increased survival. During differentiation, REST knockdown resulted in increased MAPK/ERK and WNT signaling and increased expression of mesendoderm differentiation markers. Therefore we have uncovered a new role for REST in regulation of growth and early differentiation decisions in human embryonic stem cells.

Functional interaction between hMYH and hTRADD in the TNF-α-mediated survival and death pathways of HeLa cells

Energy Technology Data Exchange (ETDEWEB)

Vy Tran, An Hue; Hahm, Soo-Hyun; Han, Se Hee [Department of Advanced Technology Fusion, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of); Chung, Ji Hyung [Department of Applied Bioscience, College of Life Science, CHA University, Gyeonggi-do 463-836 (Korea, Republic of); Park, Geon Tae [Cornell University, Ithaca, NY 14850 (United States); Han, Ye Sun, E-mail: yshan@konkuk.ac.kr [College of Global Integrated Studies, Division of Interdisciplinary Studies, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of)

2015-07-15

Highlights: • We determine the interaction between hMYH and hTRADD. • We examine changes in the level of hMYH–hTRADD interaction under TNF-α treatment. • hTRADD–hMYH association is involved in the nuclear translocation of NFκB. • hTRADD–hMYH complex influences the TNFR1–TRADD association. - Abstract: The tumor necrosis factor (TNF) signaling pathway is a classical immune system pathway that plays a key role in regulating cell survival and apoptosis. The TNF receptor-associated death domain (TRADD) protein is recruited to the death domain of TNF receptor 1 (TNFR1), where it interacts with TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP) for the induction of apoptosis, necrosis, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein (MAP) kinase activation. In this study, we found that the human MutY homolog (hMYH) interacted with human TRADD (hTRADD) via the C-terminal domain of hMYH. Moreover, under conditions promoting TNF-α-induced cell death or survival in HeLa cells, this interaction was weakened or enhanced, respectively. The interaction between hMYH and hTRADD was important for signaling pathways mediated by TNF-α. Our results also suggested that the hTRADD–hMYH association was involved in the nuclear translocation of NFκB and formation of the TNFR1–TRADD complex. Thus, this study identified a novel mechanism through which the hMYH–hTRADD interaction may affect the TNF-α signaling pathway. Implications: In HeLa cells, the hTRADD–hMYH interaction functioned in both cell survival and apoptosis pathways following TNF-α stimulation.

Helicobacter pylori-derived Heat shock protein 60 enhances angiogenesis via a CXCR2-mediated signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Lin, Chen-Si [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); He, Pei-Juin; Hsu, Wei-Tung [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Wu, Ming-Shiang [Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Wu, Chang-Jer [Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan (China); Shen, Hsiao-Wei [Institute of Molecular Medicine and Bioengineering, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Hwang, Chia-Hsiang [Yung-Shin Pharmaceutical Industry Co., Ltd., Tachia, Taichung, Taiwan (China); Lai, Yiu-Kay [Department of Life Science, Institute of Biotechnology, National Tsing Hua University, Hsin-Chu, Taiwan (China); Tsai, Nu-Man [School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Liao, Kuang-Wen, E-mail: kitchhen@yahoo.com.tw [Institute of Molecular Medicine and Bioengineering, National Chiao-Tung University, Hsin-Chu, Taiwan (China)

2010-06-25

Helicobacter pylori is a potent carcinogen associated with gastric cancer malignancy. Recently, H. pylori Heat shock protein 60 (HpHSP60) has been reported to promote cancer development by inducing chronic inflammation and promoting tumor cell migration. This study demonstrates a role for HpHSP60 in angiogenesis, a necessary precursor to tumor growth. We showed that HpHSP60 enhanced cell migration and tube formation, but not cell proliferation, in human umbilical vein endothelial cells (HUVECs). HpHSP60 also indirectly promoted HUVEC proliferation when HUVECs were co-cultured with supernatants collected from HpHSP60-treated AGS or THP-1 cells. The angiogenic array showed that HpHSP60 dramatically induced THP-1 cells and HUVECs to produce the chemotactic factors IL-8 and GRO. Inhibition of CXCR2, the receptor for IL-8 and GRO, or downstream PLC{beta}2/Ca2+-mediated signaling, significantly abolished HpHSP60-induced tube formation. In contrast, suppression of MAP K or PI3 K signaling did not affect HpHSP60-mediated tubulogenesis. These data suggest that HpHSP60 enhances angiogenesis via CXCR2/PLC{beta}2/Ca2+ signal transduction in endothelial cells.

Helicobacter pylori-derived Heat shock protein 60 enhances angiogenesis via a CXCR2-mediated signaling pathway

International Nuclear Information System (INIS)

Lin, Chen-Si; He, Pei-Juin; Hsu, Wei-Tung; Wu, Ming-Shiang; Wu, Chang-Jer; Shen, Hsiao-Wei; Hwang, Chia-Hsiang; Lai, Yiu-Kay; Tsai, Nu-Man; Liao, Kuang-Wen

2010-01-01

Helicobacter pylori is a potent carcinogen associated with gastric cancer malignancy. Recently, H. pylori Heat shock protein 60 (HpHSP60) has been reported to promote cancer development by inducing chronic inflammation and promoting tumor cell migration. This study demonstrates a role for HpHSP60 in angiogenesis, a necessary precursor to tumor growth. We showed that HpHSP60 enhanced cell migration and tube formation, but not cell proliferation, in human umbilical vein endothelial cells (HUVECs). HpHSP60 also indirectly promoted HUVEC proliferation when HUVECs were co-cultured with supernatants collected from HpHSP60-treated AGS or THP-1 cells. The angiogenic array showed that HpHSP60 dramatically induced THP-1 cells and HUVECs to produce the chemotactic factors IL-8 and GRO. Inhibition of CXCR2, the receptor for IL-8 and GRO, or downstream PLCβ2/Ca2+-mediated signaling, significantly abolished HpHSP60-induced tube formation. In contrast, suppression of MAP K or PI3 K signaling did not affect HpHSP60-mediated tubulogenesis. These data suggest that HpHSP60 enhances angiogenesis via CXCR2/PLCβ2/Ca2+ signal transduction in endothelial cells.

Inhibition of STAT3 Expression and Signaling in Resveratrol-Differentiated Medulloblastoma Cells

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Li-Jun Yu

2008-07-01

Full Text Available In this study, the potential influence of resveratrol (3,5,4′-trihydroxy-trans-stilbene in signal transducer and activator of transcription 3 (STAT3 signaling of medulloblastoma cells was evaluated by checking the status of STAT3 signaling and its downstream gene expression in two medulloblastoma cell lines (UW228-2 and UW228-3 with and without resveratrol treatment. The results revealed that resveratrol induced neuronal differentiation of medulloblastoma cells. Signal transducer and activator of transcription 3 expression and phosphorylation were detected in normally cultured UW228-2 and UW228-3 cells that were apparently attenuated after resveratrol treatment. The expression of STAT3 downstream genes, survivin, cyclin D1, Cox-2, and c-Myc, was suppressed but Bcl-2 was enhanced by resveratrol. Meanwhile, the production and secretion of leukemia inhibitory factor, a STAT3 activator, became active in resveratrol-treated cells. To further ascertain the significance of STAT3 signaling for medulloblastoma cells, AG490, a selective inhibitor of STAT3 phosphorylation, was used to treat UW228-3 cells. Phosphorylation of STAT3 was inhibited by AG490 accompanied with growth suppression, differentiation-like changes, and down-regulation of survivin, cyclin D1, Cox-2, and c-Myc. Our data thus suggest the importance of STAT3 signaling in maintenance and survival of medulloblastoma cells. This signaling may be the major target of resveratrol. Enhanced leukemia inhibitory factor and Bcl-2 expressions in resveratrol-treated cells might reflect a compensatory response to the loss of STAT3 function.

DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies.

Science.gov (United States)

Le Pogam, Carole; Patel, Satyananda; Gorombei, Petra; Guerenne, Laura; Krief, Patricia; Omidvar, Nader; Tekin, Nilgun; Bernasconi, Elena; Sicre, Flore; Schlageter, Marie-Helene; Chopin, Martine; Noguera, Maria-Elena; West, Robert; Abu, Ansu; Mathews, Vikram; Pla, Marika; Fenaux, Pierre; Chomienne, Christine; Padua, Rose Ann

2015-10-20

We have previously shown that a specific promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) DNA vaccine combined with all-trans retinoic acid (ATRA) increases the number of long term survivors with enhanced immune responses in a mouse model of acute promyelocytic leukemia (APL). This study reports the efficacy of a non-specific DNA vaccine, pVAX14Flipper (pVAX14), in both APL and high risk myelodysplastic syndrome (HR-MDS) models. PVAX14 is comprised of novel immunogenic DNA sequences inserted into the pVAX1 therapeutic plasmid. APL mice treated with pVAX14 combined with ATRA had increased survival comparable to that obtained with a specific PML-RARA vaccine. Moreover, the survival advantage correlated with decreased PML-RARA transcript levels and increase in anti-RARA antibody production. In HR-MDS mice, pVAX14 significantly improved survival and reduced biomarkers of leukemic transformation such as phosphorylated mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1. In both preclinical models, pVAX14 vaccine significantly increased interferon gamma (IFNγ) production, memory T-cells (memT), reduced the number of colony forming units (CFU) and increased expression of the adapter molecule signalling to NF-κB, MyD88. These results demonstrate the adjuvant properties of pVAX14 providing thus new approaches to improve clinical outcome in two different models of myeloid malignancies, which may have potential for a broader applicability in other cancers.

Survivability enhancement study for C/sup 3/I/BM (communications, command, control and intelligence/battle management) ground segments: Final report

Energy Technology Data Exchange (ETDEWEB)

1986-10-30

This study involves a concept developed by the Fairchild Space Company which is directly applicable to the Strategic Defense Initiative (SDI) Program as well as other national security programs requiring reliable, secure and survivable telecommunications systems. The overall objective of this study program was to determine the feasibility of combining and integrating long-lived, compact, autonomous isotope power sources with fiber optic and other types of ground segments of the SDI communications, command, control and intelligence/battle management (C/sup 3/I/BM) system in order to significantly enhance the survivability of those critical systems, especially against the potential threats of electromagnetic pulse(s) (EMP) resulting from high altitude nuclear weapon explosion(s). 28 figs., 2 tabs.

Survivability Assessment: Modeling A Recovery Process

OpenAIRE

Paputungan, Irving Vitra; Abdullah, Azween

2009-01-01

Survivability is the ability of a system to continue operating, in a timely manner, in the presence ofattacks, failures, or accidents. Recovery in survivability is a process of a system to heal or recover from damageas early as possible to fulfill its mission as condition permit. In this paper, we show a preliminary recoverymodel to enhance the system survivability. The model focuses on how we preserve the system and resumes itscritical service under attacks as soon as possible.Keywords: surv...

Laser Phototherapy Enhances Mesenchymal Stem Cells Survival in Response to the Dental Adhesives

Directory of Open Access Journals (Sweden)

Ivana Márcia Alves Diniz

2015-01-01

Full Text Available Background. We investigated the influence of laser phototherapy (LPT on the survival of human mesenchymal stem cells (MSCs submitted to substances leached from dental adhesives. Method. MSCs were isolated and characterized. Oral mucosa fibroblasts and osteoblast-like cells were used as comparative controls. Cultured medium conditioned with two adhesive systems was applied to the cultures. Cell monolayers were exposed or not to LPT. Laser irradiations were performed using a red laser (GaAlAs, 780 nm, 0.04 cm2, 40 mW, 1 W/cm2, 0.4 J, 10 seconds, 1 point, 10 J/cm2. After 24 h, cell viability was assessed by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide reduction assay. Data were statistically compared by ANOVA followed by Tukey’s test (P<0.05. Results. Different cell types showed different viabilities in response to the same materials. Substances leached from adhesives were less cytotoxic to MSCs than to other cell types. Substances leached from Clearfil SE Bond were highly cytotoxic to all cell types tested, except to the MSCs when applied polymerized and in association with LPT. LPT was unable to significantly increase the cell viability of fibroblasts and osteoblast-like cells submitted to the dental adhesives. Conclusion. LPT enhances mesenchymal stem cells survival in response to substances leached from dental adhesives.

Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling

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Cecilie Linneberg

2015-09-01

Full Text Available In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.

Dying to remember, remembering to survive: mortality salience and survival processing.

Science.gov (United States)

Burns, Daniel J; Hart, Joshua; Kramer, Melanie E; Burns, Amy D

2014-01-01

Processing items for their relevance to survival improves recall for those items relative to numerous other deep processing encoding techniques. Perhaps related, placing individuals in a mortality salient state has also been shown to enhance retention of items encoded after the morality salience manipulation (e.g., in a pleasantness rating task), a phenomenon we dubbed the "dying-to-remember" (DTR) effect. The experiments reported here further explored the effect and tested the possibility that the DTR effect is related to survival processing. Experiment 1 replicated the effect using different encoding tasks, demonstrating that the effect is not dependent on the pleasantness task. In Experiment 2 the DTR effect was associated with increases in item-specific processing, not relational processing, according to several indices. Experiment 3 replicated the main results of Experiment 2, and tested the effects of mortality salience and survival processing within the same experiment. The DTR effect and its associated difference in item-specific processing were completely eliminated when the encoding task required survival processing. These results are consistent with the interpretation that the mechanisms responsible for survival processing and DTR effects are overlapping.

Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling

International Nuclear Information System (INIS)

Deep, Gagan; Kumar, Rahul; Jain, Anil K.; Agarwal, Chapla; Agarwal, Rajesh

2014-01-01

Highlights: • Silibinin inhibits fibronectin-induce motile morphology in PC3 cells. • Silibinin inhibits fibronectin-induced migration and invasion in PC3 cells. • Silibinin targets fibronectin-induced integrins and downstream signaling molecule. - Abstract: Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell–cell interaction with integrins-based cell–matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells’ interaction with extracellular matrix component fibronectin. Silibinin (50–200 μM) treatment significantly decreased the fibronectin (5 μg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin-treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (α5, αV, β1 and β3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and

Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling

Energy Technology Data Exchange (ETDEWEB)

Deep, Gagan [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States); Kumar, Rahul; Jain, Anil K. [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Agarwal, Chapla [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States); Agarwal, Rajesh, E-mail: Rajesh.agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO (United States)

2014-10-15

Highlights: • Silibinin inhibits fibronectin-induce motile morphology in PC3 cells. • Silibinin inhibits fibronectin-induced migration and invasion in PC3 cells. • Silibinin targets fibronectin-induced integrins and downstream signaling molecule. - Abstract: Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell–cell interaction with integrins-based cell–matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells’ interaction with extracellular matrix component fibronectin. Silibinin (50–200 μM) treatment significantly decreased the fibronectin (5 μg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin-treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (α5, αV, β1 and β3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and

Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

International Nuclear Information System (INIS)

Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae

2012-01-01

Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae, E-mail: chidkim@pusan.ac.kr

2012-04-01

Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

Sodium nitroprusside enhanced cardiopulmonary resuscitation improves short term survival in a porcine model of ischemic refractory ventricular fibrillation.

Science.gov (United States)

Yannopoulos, Demetris; Bartos, Jason A; George, Stephen A; Sideris, George; Voicu, Sebastian; Oestreich, Brett; Matsuura, Timothy; Shekar, Kadambari; Rees, Jennifer; Aufderheide, Tom P

2017-01-01

Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. SNPeCPR will increase short term (4-h) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5min. Basic life support was performed for 10min. At minute 10 (EMS arrival), animals received either SNPeCPR (n=8) or standard ACLS (n=8). Defibrillation (200J) occurred every 3min. CPR continued for a total of 45min, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60min, if unsuccessful. SNPeCPR animals received 2mg of SNP at minute 10 followed by 1mg every 5min until ROSC. Standard ACLS animals received 0.5mg epinephrine every 5min until ROSC. Primary endpoints were ROSC and 4-h survival. All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p=0.04). The 4-h survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p=0.0019. SNPeCPR significantly improved ROSC and 4-h survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer

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Collin M. Blakely

2015-04-01

Full Text Available Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.

Wnt/β-catenin signaling activates nephronectin expression in osteoblasts

International Nuclear Information System (INIS)

Ikehata, Mikiko; Yamada, Atsushi; Morimura, Naoko; Itose, Masakatsu; Suzawa, Tetsuo; Shirota, Tatsuo; Chikazu, Daichi; Kamijo, Ryutaro

2017-01-01

Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles as an adhesion molecule in the development and functions of various organs and tissues, such as the kidneys and bone. In the present study, we found that Wnt3a strongly enhanced Npnt mRNA expression in osteoblast-like MC3T3-E1 cells, while it also induced an increase in Npnt gene expression in both time- and dose-dependent manners via the Wnt/β-catenin signaling pathway. These results suggest novel mechanisms for Wnt3a-induced osteoblast proliferation and cell survival via Npnt gene expression. - Highlights: • Wnt3a enhances nephronectin gene expression. • Nephronectin gene induction by Wnt3a is occurred by time- and dose-dependent manner. • Expression of nephronectin is regulated via β-catenin activation.

Proton nuclear magnetic resonance imaging of regionally ischemic canine hearts: effects of paramagnetic proton signal enhancement

International Nuclear Information System (INIS)

Brady, T.J.; Goldman, M.R.; Pykett, I.L.; Buonanno, F.S.; Kistler, J.P.; Newhouse, J.H.; Burt, C.T.; Hinshaw, W.S.; Pohost, G.M.

1982-01-01

In a study to evaluate the potential of proton nuclear magnetic resonance (NMR) imaging with and without manganese contrast enhancement for detecting acute myocardial infarction, 12 dogs underwent 90-minute occlusion of the left circumflex coronary artery. Transverse-section NMR images of the excised, nonbeating heart were obtained at 1-cm intervals using the steady-state-free-precession (SSFP) technique. All NMR images revealed detailed structure of the heart. The three hearts without manganese showed no difference in intensity between the normal and the ischemic posterior regions, whereas those with manganese demonstrated a clearly demarcated zone of reduced signal intensity consistent with the ischemic zone. It is concluded that high-resolution tomograms of the excised canine myocardium can be obtained using proton NMR imaging. With the SSFP imaging technique, proton signal enhancement with manganese infusion is necessary to differentiate between ischemic and nonischemic myocardium after 90 minutes of coronary occlusion

Local readout enhancement for detuned signal-recycling interferometers

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Rehbein, Henning; Mueller-Ebhardt, Helge; Schnabel, Roman; Danzmann, Karsten; Somiya, Kentaro; Chen Yanbei; Li Chao

2007-01-01

High power detuned signal-recycling interferometers currently planned for second-generation interferometric gravitational-wave detectors (for example Advanced LIGO) are characterized by two resonances in the detection band, an optical resonance and an optomechanical resonance which is upshifted from the suspension pendulum frequency due to the so-called optical-spring effect. The detector's sensitivity is enhanced around these two resonances. However, at frequencies below the optomechanical resonance frequency, the sensitivity of such interferometers is significantly lower than non-optical-spring configurations with comparable circulating power; such a drawback can also compromise high-frequency sensitivity, when an optimization is performed on the overall sensitivity of the interferometer to a class of sources. In this paper, we clarify the reason for such a low sensitivity, and propose a way to fix this problem. Motivated by the optical-bar scheme of Braginsky, Gorodetsky, and Khalili, we propose to add a local readout scheme which measures the motion of the arm-cavity front mirror, which at low frequencies moves together with the arm-cavity end mirror, under the influence of gravitational waves. This scheme improves the low-frequency quantum-noise-limited sensitivity of optical-spring interferometers significantly and can be considered as an incorporation of the optical-bar scheme into currently planned second-generation interferometers. On the other hand it can be regarded as an extension of the optical-bar scheme. Taking compact binary inspiral signals as an example, we illustrate how this scheme can be used to improve the sensitivity of the planned Advanced LIGO interferometer, in various scenarios, using a realistic classical-noise budget. We also discuss how this scheme can be implemented in Advanced LIGO with relative ease

CYP2S1 depletion enhances colorectal cell proliferation is associated with PGE2-mediated activation of β-catenin signaling

International Nuclear Information System (INIS)

Yang, Chao; Li, Changyuan; Li, Minle; Tong, Xuemei; Hu, Xiaowen; Yang, Xuhan; Yan, Xiaomei; He, Lin; Wan, Chunling

2015-01-01

Colorectal epithelial cancer is one of the most common cancers in the world and its 5-year survival rate is still relatively low. Cytochrome P450 (CYP) enzymes in epithelial cells lining the alimentary tract play an important role in the oxidative metabolism of a wide range of xenobiotics, including (pro-)carcinogens and endogenous compounds. Although CYP2S1, a member of CYP family, strongly expressed in many extrahepatic tissues, the role of CYP2S1 in cancer remains unclear. To investigate whether CYP2S1 involves in colorectal carcinogenesis, cell proliferation was analyzed in HCT116 cells depleted of CYP2S1 using small hairpin interfering RNA. Our data show that CYP2S1 knockdown promotes cell proliferation through increasing the level of endogenous prostaglandin E2(PGE2). PGE2, in turn, reduces phosphorylation of β-catenin and activates β-catenin signaling, which contributes to the cell proliferation. Furthermore, CYP2S1 knockdown increase tumor growth in xenograft mouse model. In brief, these results demonstrate that CYP2S1 regulates colorectal cancer growth through associated with PGE2-mediated activation of β-catenin signaling. - Highlights: • Knockdown of CYP2S1 expression improve HCT116 cell proliferation in vitro and in vivo. • Elevate PGE2 production in CYP2S1 knockdown cell is associated with its proliferation. • Elevate PGE2 level in CYP2S1 knockdown cells enhance β-catenin accumulation. • β-catenin activate TCF/LEF and target gene expression thus promote cell proliferation

CYP2S1 depletion enhances colorectal cell proliferation is associated with PGE2-mediated activation of β-catenin signaling

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Yang, Chao [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); College of Life Science, Anhui Normal University, Wuhu 241000, Anhui (China); Li, Changyuan [College of Life Science, Anhui Normal University, Wuhu 241000, Anhui (China); Li, Minle; Tong, Xuemei [Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China); Hu, Xiaowen; Yang, Xuhan [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); Yan, Xiaomei [School of Life Sciences & Biotechnology, Shanghai JiaoTong University, Shanghai 200240 (China); He, Lin, E-mail: helinhelin@gmail.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); Wan, Chunling, E-mail: clwan@sjtu.edu.cn [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China)

2015-02-15

Colorectal epithelial cancer is one of the most common cancers in the world and its 5-year survival rate is still relatively low. Cytochrome P450 (CYP) enzymes in epithelial cells lining the alimentary tract play an important role in the oxidative metabolism of a wide range of xenobiotics, including (pro-)carcinogens and endogenous compounds. Although CYP2S1, a member of CYP family, strongly expressed in many extrahepatic tissues, the role of CYP2S1 in cancer remains unclear. To investigate whether CYP2S1 involves in colorectal carcinogenesis, cell proliferation was analyzed in HCT116 cells depleted of CYP2S1 using small hairpin interfering RNA. Our data show that CYP2S1 knockdown promotes cell proliferation through increasing the level of endogenous prostaglandin E2(PGE2). PGE2, in turn, reduces phosphorylation of β-catenin and activates β-catenin signaling, which contributes to the cell proliferation. Furthermore, CYP2S1 knockdown increase tumor growth in xenograft mouse model. In brief, these results demonstrate that CYP2S1 regulates colorectal cancer growth through associated with PGE2-mediated activation of β-catenin signaling. - Highlights: • Knockdown of CYP2S1 expression improve HCT116 cell proliferation in vitro and in vivo. • Elevate PGE2 production in CYP2S1 knockdown cell is associated with its proliferation. • Elevate PGE2 level in CYP2S1 knockdown cells enhance β-catenin accumulation. • β-catenin activate TCF/LEF and target gene expression thus promote cell proliferation.

Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis

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J. Travis Hinson

2016-12-01

Full Text Available AMP-activated protein kinase (AMPK is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGFβ isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFβ signaling.

Lack of Outer Membrane Protein A Enhances the Release of Outer Membrane Vesicles and Survival of Vibrio cholerae and Suppresses Viability of Acanthamoeba castellanii

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Soni Priya Valeru

2014-01-01

Full Text Available Vibrio cholerae, the causative agent of the diarrhoeal disease cholera, survives in aquatic environments. The bacterium has developed a survival strategy to grow and survive inside Acanthamoeba castellanii. It has been shown that V. cholerae expresses outer membrane proteins as virulence factors playing a role in the adherence to interacted host cells. This study examined the role of outer membrane protein A (OmpA and outer membrane vesicles (OMVs in survival of V. cholerae alone and during its interaction with A. castellanii. The results showed that an OmpA mutant of V. cholerae survived longer than wild-type V. cholerae when cultivated alone. Cocultivation with A. castellanii enhanced the survival of both bacterial strains and OmpA protein exhibited no effect on attachment, engulfment, and survival inside the amoebae. However, cocultivation of the OmpA mutant of V. cholerae decreased the viability of A. castellanii and this bacterial strain released more OMVs than wild-type V. cholerae. Surprisingly, treatment of amoeba cells with OMVs isolated from the OmpA mutant significantly decreased viable counts of the amoeba cells. In conclusion, the results might highlight a regulating rule for OmpA in survival of V. cholerae and OMVs as a potent virulence factor for this bacterium towards eukaryotes in the environment.

Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer.

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Bernard, Pascal; Ryan, Janelle; Sim, Helena; Czech, Daniel P; Sinclair, Andrew H; Koopman, Peter; Harley, Vincent R

2012-02-01

Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.

Natural exopolysaccharides enhance survival of lactic acid bacteria in frozen dairy desserts.

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Hong, S H; Marshall, R T

2001-06-01

Viable lactic acid-producing bacteria in frozen dairy desserts can be a source of beta-galactosidase for persons who absorb lactose insufficiently. However, freezing kills many of the cells, causing loss of enzymatic activity. Cultures selected for high beta-galactosidase activities and high survival rates in the presence of bile were examined for survivability during freezing in reduced-fat ice cream. Encapsulated S. thermophilus strains survived better than their nonencapsulated mutants in reduced-fat ice cream after freezing and frozen storage at -29 degrees C for 16 d (28 vs. 19%). However, a small nonencapsulated strain of Lactobacillus delbrueckii sp. bulgaricus survived better than the large encapsulated strain in reduced-fat ice cream. Factors that improved survival of encapsulated S. thermophilus 1068 in ice cream were 1) harvest of cells in the late-log phase of growth at 37 degrees C rather than at 40, 42.5, or 45 degrees C; 2) overrun at 50% rather than 100%; and 3) storage at -17 degrees C rather than -23 or -29 degrees C. Survival of strain ST1068 was unaffected by 1) neutralization of acid during growth or 2) substitution of nitrogen for air in building overrun.

Bumblebee family lineage survival is enhanced in high-quality landscapes.

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Carvell, Claire; Bourke, Andrew F G; Dreier, Stephanie; Freeman, Stephen N; Hulmes, Sarah; Jordan, William C; Redhead, John W; Sumner, Seirian; Wang, Jinliang; Heard, Matthew S

2017-03-23

Insect pollinators such as bumblebees (Bombus spp.) are in global decline. A major cause of this decline is habitat loss due to agricultural intensification. A range of global and national initiatives aimed at restoring pollinator habitats and populations have been developed. However, the success of these initiatives depends critically upon understanding how landscape change affects key population-level parameters, such as survival between lifecycle stages, in target species. This knowledge is lacking for bumblebees, because of the difficulty of systematically finding and monitoring colonies in the wild. We used a combination of habitat manipulation, land-use and habitat surveys, molecular genetics and demographic and spatial modelling to analyse between-year survival of family lineages in field populations of three bumblebee species. Here we show that the survival of family lineages from the summer worker to the spring queen stage in the following year increases significantly with the proportion of high-value foraging habitat, including spring floral resources, within 250-1,000 m of the natal colony. This provides evidence for a positive impact of habitat quality on survival and persistence between successive colony cycle stages in bumblebee populations. These findings also support the idea that conservation interventions that increase floral resources at a landscape scale and throughout the season have positive effects on wild pollinators in agricultural landscapes.

Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling.

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Nagendran, Tharkika; Larsen, Rylan S; Bigler, Rebecca L; Frost, Shawn B; Philpot, Benjamin D; Nudo, Randolph J; Taylor, Anne Marion

2017-09-20

Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.Spinal cord injury can induce synaptic reorganization and remodeling in the brain. Here the authors study how severed distal axons signal back to the cell body to induce hyperexcitability, loss of inhibition and enhanced presynaptic release through netrin-1.

AKT signaling mediates IGF-I survival actions on otic neural progenitors.

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Maria R Aburto

Full Text Available BACKGROUND: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I, through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K. Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of organotypic cultures of chicken (Gallus gallus otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1 transcription factor. By contrast, our results indicate that post-mitotic p27(Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. CONCLUSIONS/SIGNIFICANCE: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor.

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Bolnick, Alan D; Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza; Kilburn, Brian A; Pasalodos, Omar J; Singhal, Pankaj K; Dai, Jing; Diamond, Michael P; Armant, D Randall; Drewlo, Sascha

2017-06-01

Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB

Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats.

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Stern, Javier E; Potapenko, Evgeniy S

2013-08-15

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.

Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium.

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Peng, Lin; Yu, Xiao; Li, Chengyuan; Cai, Yanfei; Chen, Yun; He, Yang; Yang, Jianfeng; Jin, Jian; Li, Huazhong

2016-04-01

Signal peptides play an important role in directing and efficiently transporting secretory proteins to their proper locations in the endoplasmic reticulum of mammalian cells. The aim of this study was to enhance the expression of recombinant coagulation factor VII (rFVII) in CHO cells by optimizing the signal peptides and type of fed-batch culture medium used. Five sub-clones (O2, I3, H3, G2 and M3) with different signal peptide were selected by western blot (WB) analysis and used for suspension culture. We compared rFVII expression levels of 5 sub-clones and found that the highest rFVII expression level was obtained with the IgK signal peptide instead of Ori, the native signal peptide of rFVII. The high protein expression of rFVII with signal peptide IgK was mirrored by a high transcription level during suspension culture. After analyzing culture and feed media, the combination of M4 and F4 media yielded the highest rFVII expression of 20 mg/L during a 10-day suspension culture. After analyzing cell density and cell cycle, CHO cells feeding by F4 had a similar percentage of cells in G0/G1 and a higher cell density compared to F2 and F3. This may be the reason for high rFVII expression in M4+F4. In summary, rFVII expression was successfully enhanced by optimizing the signal peptide and fed-batch medium used in CHO suspension culture. Our data may be used to improve the production of other therapeutic proteins in fed-batch culture.

Transplantation of cord blood mesenchymal stem cells as spheroids enhances vascularization.

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Bhang, Suk Ho; Lee, Seahyoung; Shin, Jung-Youn; Lee, Tae-Jin; Kim, Byung-Soo

2012-10-01

Despite promising results from the therapeutic use of stem cells for treating ischemic diseases, the poor survival of cells transplanted into ischemic regions is one of the major problems that undermine the efficacy of stem cell therapy. Cord blood mononuclear cells (CBMNCs) are an alternative source of mesenchymal stem cells (MSCs) without disadvantages, such as the painful and invasive harvesting procedure, of MSCs derived from bone marrow or adipose tissue. In the present study, we investigated whether the angiogenic efficacy of cord blood mesenchymal stem cells (CBMSCs) can be enhanced by grafting as spheroids in a mouse hindlimb ischemia model. Human CBMSC (hCBMSC) spheroids were prepared by using the hanging-drop method. Mouse hindlimb ischemia was induced by excising the femoral artery and its branches. After surgery, the animals were divided into no-treatment, dissociated hCBMSC, and spheroid hCBMSC groups (n=8 per group) and received corresponding hCBMSC treatments. After surgery, the ischemic hindlimbs were monitored for 4 weeks, and then, the ischemic hindlimb muscles were harvested for histological analysis. Apoptotic signaling, angiogenesis-related signal pathways, and blood vessel formation were investigated in vitro and/or in vivo. The transplantation of hCBMSCs as spheroids into mouse ischemic hindlimbs significantly improved the survival of the transplanted cells by suppressing apoptotic signaling while activating antiapoptotic signaling. Furthermore, the transplantation of hCBMSCs as spheroids significantly increased the number of microvessels and smooth muscle α-actin-positive vessels in the ischemic limbs of mice, and attenuated limb loss and necrosis. Human CBMNC can be considered an alternative source of MSC, and spheroid-based hCBMSC delivery can be considered a simple and effective strategy for enhancing the therapeutic efficacy of hCBMSCs.

Prevalence and signal characteristics of late gadolinium enhancement on contrast-enhanced magnetic resonance imaging in patients with takotsubo cardiomyopathy

International Nuclear Information System (INIS)

Nakamori, Shiro; Matsuoka, Koji; Onishi, Katsuya

2012-01-01

The background of this study was to determine the prevalence and signal intensity (SI) characteristics of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) in takotsubo cardiomyopathy (TC). Cine, black-blood T2-weighted and LGE MR images were acquired in 23 patients with TC within 72h of onset. Wall motion abnormality (WMA), edema and LGE were evaluated with a 16-segment model. The SI characteristics of LGE were analyzed using SI distribution in remote normal segments as reference. Follow-up MRI was performed 3 months later. Retrospective analysis of LGE MRI was also performed in 10 patients with acute myocardial infarction (AMI) to compare the SI characteristics between TC and AMI. In acute phase, WMA and edema were observed in 236 (64%) and 205 (56%) of 368 segments. LGE was observed in 10 (2.7%) of 368 segments and in 5 (22%) of 23 patients. All LGE lesions in TC exhibited transmural enhancement. The contrast-to-noise ratio (CNR) in TC was significantly lower than that of AMI (3.1±0.3 standard deviations (SD) vs. 6.1±1.2 SD, P<0.01), and CNR value of 4 was useful for distinguishing TC from AMI. Both LGE and WMA disappeared within 12 months. Grey myocardial signal on LGE MRI may be observed in patients with TC. However, the extent of LGE is substantially less than that of WMA and edema, and disappears within 12 months. (author)

Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation

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Olivia Alder

2014-10-01

Full Text Available Summary: Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines. : It is unclear how key transcription factors are critical for both lineage specification during embryonic development and maintenance of a differentiated, adult phenotype. By profiling the enhancer occupancy of the key transcription factors HNF4A and FOXA2 during mouse liver development, Alder et al. have found that YAP1 can influence enhancer interactions and target gene expression levels. Enhancer switching enables HNF4A and FOXA2 to fulfill distinct roles during organ development.

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.

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Cheng, Liang; Ma, Jianping; Li, Jingyun; Li, Dan; Li, Guangming; Li, Feng; Zhang, Qing; Yu, Haisheng; Yasui, Fumihiko; Ye, Chaobaihui; Tsao, Li-Chung; Hu, Zhiyuan; Su, Lishan; Zhang, Liguo

2017-01-03

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival.

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Lok, James B

2016-12-01

Signaling or communication between host and parasite may occur over relatively long ranges to enable host finding and acquisition by infective parasitic nematode larvae. Innate behaviors in infective larvae transmitted from the soil that enhance the likelihood of host contact, such as negative geotaxis and hypermotility, are likely mediated by mechanoreception and neuromuscular signaling. Host cues such as vibration of the substratum, elevated temperature, exhaled CO 2 , and other volatile odorants are perceived by mechanosensory and chemosensory neurons of the amphidial complex. Beyond this, the molecular systems that transduce these external cues within the worm are unknown at this time. Overall, the signal transduction mechanisms that regulate switching between dauer and continuous reproductive development in Caenorhabditis elegans , and doubtless other free-living nematodes, have provided a useful framework for testing hypotheses about how the morphogenesis and development of infective parasitic nematode larvae and the lifespan of adult parasites are regulated. In C. elegans , four major signal transduction pathways, G protein-coupled receptor signaling, insulin/insulin-like growth factor signaling, TGFβ-like signaling and steroid-nuclear hormone receptor signaling govern the switch between dauer and continuous development and regulate adult lifespan. Parasitic nematodes appear to have conserved the functions of G-protein-coupled signaling, insulin-like signaling and steroid-nuclear hormone receptor signaling to regulate larval development before and during the infective process. By contrast, TGFβ-like signaling appears to have been adapted for some other function, perhaps modulation of the host immune response. Of the three signal transduction pathways that appear to regulate development in parasitic nematodes, steroid-nuclear hormone signaling is the most straightforward to manipulate with administered small molecules and may form the basis of new

The Role of Local Governmental Funding in Nonprofit Survival

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Karl Besel

2001-05-01

Full Text Available Nonprofit social service organizations in America originally relied on private donations and charitable events to sustain their operations. As the number of nonprofit organizations has proliferated over the last few decades, so has nonprofit dependency on governmental and other sources of revenue. A case study design was used to examine factors that have impacted the survival of the original Indiana Youth Service Bureaus. This study highlights salient factors that influence survival and explores the characteristics and circumstances of selected organizations that enhance their sustainability. The findings suggest that social work administrators need to foster long-term relationships with local funders as a means of enhancing organizational survival.

Appearance of high signal intensity and gadolinium-DTPA contrast enhancement in hypertrophied myocardium by magnetic resonance imaging

International Nuclear Information System (INIS)

Nishimura, Tsunehiko; Yamada, Naoaki; Nagata, Seiki

1989-01-01

This study was undertaken to examine the potential role of magnetic resonance imaging (MRI) for evaluating myocardial tissue characterization in hypertrophic cardiomyopathy (HCM). ECG-gated MRI images were acquired in 32 HCM patients and 30 patients with hypertensive heart disease (HHD), using a 1.5 T superconducting magnet system. The thickened areas were depicted as high signal intensities in the septum of 12 HCM patients (38%) and the endocardium of 5 HHD patients (17%). Echocardiography revealed that MRI appearance of high signal intensity was associated with more thickened myocardial wall. For evaluable 16 patients receiving i.v. injection of Gd-DTPA in a dose of 0.1 mM/kg, enhancement effects were observed in 10 patients (63%). High signal intensity appearing in the hypertrophied myocardium, as well as contrast enhancement, may not be characteristic of HCM, but reflect the likelihood of myocardial degeneration associated with the hypertrophied myocardium. Although MRI may not be capable of differentiating tissue characterization in HCM from that in HHD, it may provide different information about tissue characterization in the hypertrophied myocardium from that obtained by other techniques. (N.K.)

Dynamic Contrast-Enhanced MRI of Cervical Cancers: Temporal Percentile Screening of Contrast Enhancement Identifies Parameters for Prediction of Chemoradioresistance

International Nuclear Information System (INIS)

Andersen, Erlend K.F.; Hole, Knut Håkon; Lund, Kjersti V.; Sundfør, Kolbein; Kristensen, Gunnar B.; Lyng, Heidi; Malinen, Eirik

2012-01-01

Purpose: To systematically screen the tumor contrast enhancement of locally advanced cervical cancers to assess the prognostic value of two descriptive parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods and Materials: This study included a prospectively collected cohort of 81 patients who underwent DCE-MRI with gadopentetate dimeglumine before chemoradiotherapy. The following descriptive DCE-MRI parameters were extracted voxel by voxel and presented as histograms for each time point in the dynamic series: normalized relative signal increase (nRSI) and normalized area under the curve (nAUC). The first to 100th percentiles of the histograms were included in a log-rank survival test, resulting in p value and relative risk maps of all percentile–time intervals for each DCE-MRI parameter. The maps were used to evaluate the robustness of the individual percentile–time pairs and to construct prognostic parameters. Clinical endpoints were locoregional control and progression-free survival. The study was approved by the institutional ethics committee. Results: The p value maps of nRSI and nAUC showed a large continuous region of percentile–time pairs that were significantly associated with locoregional control (p < 0.05). These parameters had prognostic impact independent of tumor stage, volume, and lymph node status on multivariate analysis. Only a small percentile–time interval of nRSI was associated with progression-free survival. Conclusions: The percentile–time screening identified DCE-MRI parameters that predict long-term locoregional control after chemoradiotherapy of cervical cancer.

Testin, a novel binding partner of the calcium-sensing receptor, enhances receptor-mediated Rho-kinase signalling

International Nuclear Information System (INIS)

Magno, Aaron L.; Ingley, Evan; Brown, Suzanne J.; Conigrave, Arthur D.; Ratajczak, Thomas; Ward, Bryan K.

2011-01-01

Highlights: → A yeast two-hybrid screen revealed testin bound to the calcium-sensing receptor. → The second zinc finger of LIM domain 1 of testin is critical for interaction. → Testin bound to a region of the receptor tail important for cell signalling. → Testin and receptor interaction was confirmed in mammalian (HEK293) cells. → Overexpression of testin enhanced receptor-mediated Rho signalling in HEK293 cells. -- Abstract: The calcium-sensing receptor (CaR) plays an integral role in calcium homeostasis and the regulation of other cellular functions including cell proliferation and cytoskeletal organisation. The multifunctional nature of the CaR is manifested through ligand-dependent stimulation of different signalling pathways that are also regulated by partner binding proteins. Following a yeast two-hybrid library screen using the intracellular tail of the CaR as bait, we identified several novel binding partners including the focal adhesion protein, testin. Testin has not previously been shown to interact with cell surface receptors. The sites of interaction between the CaR and testin were mapped to the membrane proximal region of the receptor tail and the second zinc-finger of LIM domain 1 of testin, the integrity of which was found to be critical for the CaR-testin interaction. The CaR-testin association was confirmed in HEK293 cells by coimmunoprecipitation and confocal microscopy studies. Ectopic expression of testin in HEK293 cells stably expressing the CaR enhanced CaR-stimulated Rho activity but had no effect on CaR-stimulated ERK signalling. These results suggest an interplay between the CaR and testin in the regulation of CaR-mediated Rho signalling with possible effects on the cytoskeleton.

Clay mineral type effect on bacterial enteropathogen survival in soil.

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Brennan, Fiona P; Moynihan, Emma; Griffiths, Bryan S; Hillier, Stephen; Owen, Jason; Pendlowski, Helen; Avery, Lisa M

2014-01-15

Enteropathogens released into the environment can represent a serious risk to public health. Soil clay content has long been known to have an important effect on enteropathogen survival in soil, generally enhancing survival. However, clay mineral composition in soils varies, and different clay minerals have specific physiochemical properties that would be expected to impact differentially on survival. This work investigated the effect of clay materials, with a predominance of a particular mineral type (montmorillonite, kaolinite, or illite), on the survival in soil microcosms over 96 days of Listeria monocytogenes, Salmonella Dublin, and Escherichia coli O157. Clay mineral addition was found to alter a number of physicochemical parameters in soil, including cation exchange capacity and surface area, and this was specific to the mineral type. Clay mineral addition enhanced enteropathogen survival in soil. The type of clay mineral was found to differentially affect enteropathogen survival and the effect was enteropathogen-specific. © 2013.

Central high signal in inflammatory swollen lymph nodes on SPIO-enhanced interstitial MR lymphograms. A mimic of lymph node metastasis

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Suzuki, Daisuke; Yamaguchi, Masayuki; Furuta, Toshihiro; Fujii, Hirofumi; Okuyama, Yasuo; Yoshikawa, Kohki

2012-01-01

This study demonstrates that the central high signal which has been considered to be useful for the differential diagnosis of inflammation and metastasis in SPIO (super-paramagnetic iron oxide)-enhanced interstitial MR lymphography, is observable even in the simple inflammation of the lymph node (LN),. Lymphadenitis was induced by injection of Freund's complete adjuvant in the foot pad of 10 ddY mice, where ferucarbotran (a clinical SPIO agent) at 0.17 micro-moles Fe/foot in 6 mice or the control saline in 4 mice was administered 2 weeks later. Lipid-suppressed T2-weighted fast-spin-echo images (T2WIs) were acquired (retention time/effective echo time 4000/60 ms: resolution 78 x 78 x 1000 micro-m 3 ) of the popliteal LN in vivo and ex vivo using 3T whole body scanner (Signa HDx) with a radiofrequency coil dedicated to mice. Areas of high signal crossing the LN center on the in vivo transverse T2WIs were measured to evaluate non-enhanced areas quantitatively. Iron deposit in LNs was evaluated by Prussian blue staining. In mice given SPIO, the mean area of high signal was 3.9 mm 2 vs 11.3 in those given the saline, low signal in the periphery in 6/6 mice vs 0/4, ex vivo low signal in the whole area in 1 case vs 0 and periphery in 5 cases vs 0, and iron deposit in the whole in 2 cases vs 0 and periphery in 4 cases vs 0, respectively. The finding indicates that a central high signal in swollen sentinel LNs in clinical SPIO-enhanced interstitial MR lymphography with a high magnetic field does not always mean the presence of metastatic foci. (T.T.)

Bacillus licheniformis Isolated from Traditional Korean Food Resources Enhances the Longevity of Caenorhabditis elegans through Serotonin Signaling.

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Park, Mi Ri; Oh, Sangnam; Son, Seok Jun; Park, Dong-June; Oh, Sejong; Kim, Sae Hun; Jeong, Do-Youn; Oh, Nam Su; Lee, Youngbok; Song, Minho; Kim, Younghoon

2015-12-02

In this study, we investigated potentially probiotic Bacillus licheniformis strains isolated from traditional Korean food sources for ability to enhance longevity using the nematode Caenorhabditis elegans as a simple in vivo animal model. We first investigated whether B. licheniformis strains were capable of modulating the lifespan of C. elegans. Among the tested strains, preconditioning with four B. licheniformis strains significantly enhanced the longevity of C. elegans. Unexpectedly, plate counting and transmission electron microscopy (TEM) results indicated that B. licheniformis strains were not more highly attached to the C. elegans intestine compared with Escherichia coli OP50 or Lactobacillus rhamnosus GG controls. In addition, qRT-PCR and an aging assay with mutant worms showed that the conditioning of B. licheniformis strain 141 directly influenced genes associated with serotonin signaling in nematodes, including tph-1 (tryptophan hydroxylase), bas-1 (serotonin- and dopamine-synthetic aromatic amino acid decarboxylase), mod-1 (serotonin-gated chloride channel), ser-1, and ser-7 (serotonin receptors) during C. elegans aging. Our findings suggest that B. licheniformis strain 141, which is isolated from traditional Korean foods, is a probiotic generally recognized as safe (GRAS) strain that enhances the lifespan of C. elegans via host serotonin signaling.

DEAD-box helicase 27 promotes colorectal cancer growth and metastasis and predicts poor survival in CRC patients.

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Tang, Jieting; Chen, Huarong; Wong, Chi-Chun; Liu, Dabin; Li, Tong; Wang, Xiaohong; Ji, Jiafu; Sung, Joseph Jy; Fang, Jing-Yuan; Yu, Jun

2018-03-14

Copy number alterations (CNAs) are crucial for colorectal cancer (CRC) development. In this study, DEAD box polypeptide 27 (DDX27) was identified to be highly amplified in both TCGA CRC (474/615) and primary CRC (47/103), which was positively correlated with its mRNA overexpression. High DDX27 mRNA (N = 199) and protein expression (N = 260) predicted poor survival in CRC patients. Ectopic expression of DDX27 increased CRC cells proliferation, migration and invasion, but suppressed apoptosis. Conversely, silencing of DDX27 exerted opposite effects in vitro and significantly inhibited murine xenograft tumor growth and lung metastasis in vivo. Up-regulation of DDX27 enhanced and prolonged TNF-α-mediated NF-κB signaling. Nucleophosmin (NPM1) was identified as a binding partner of DDX27. DDX27 increased nuclear NPM1 and NF-κB-p65 interaction to enhance DNA binding activity of NF-κB. Silencing NPM1 abrogated DDX27-activating NF-κB signaling and its tumor-promoting function. Together, DDX27 is overexpressed and plays a pivotal oncogenic role in CRC.

HSP27 phosphorylation modulates TRAIL-induced activation of Src-Akt/ERK signaling through interaction with β-arrestin2.

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Qi, Shimei; Xin, Yinqiang; Qi, Zhilin; Xu, Yimiao; Diao, Ying; Lan, Lei; Luo, Lan; Yin, Zhimin

2014-03-01

Heat shock protein 27 (HSP27) regulates critical cellular functions such as development, differentiation, cell growth and apoptosis. A variety of stimuli induce the phosphorylation of HSP27, which affects its cellular functions. However, most previous studies focused on the role of HSP27 protein itself in apoptosis, the particular role of its phosphorylation state in signaling transduction remains largely unclear. In the present study, we reported that HSP27 phosphorylation modulated TRAIL-triggered pro-survival signaling transduction. In HeLa cells, suppression of HSP27 phosphorylation by specific inhibitor KRIBB3 or MAPKAPK2 (MK2) knockdown and by overexpression of non-phosphorylatable HSP27(3A) mutant demonstrated that hindered HSP27 phosphorylation enhanced the TRAIL-induced apoptosis. In addition, reduced HSP27 phosphorylation by KRIBB3 treatment or MK2 knockdown attenuated the TRAIL-induced activation of Akt and ERK survival signaling through suppressing the phosphorylation of Src. By overexpression of HSP27(15A) or HSP27(78/82A) phosphorylation mutant, we further showed that phosphorylation of HSP27 at serine 78/82 residues was essential to TRAIL-triggered Src-Akt/ERK signaling transduction. Co-immunoprecipitation and confocal microscopy showed that HSP27 interacted with Src and scaffolding protein β-arrestin2 in response of TRAIL stimulation and suppression of HSP27 phosphorylation apparently disrupted the TRAIL-induced interaction of HSP27 and Src or interaction of HSP27 and β-arrestin2. We further demonstrated that β-arrestin2 mediated HSP27 action on TRAIL-induced Src activation, which was achieved by recruiting signaling complex of HSP27/β-arrestin2/Src in response to TRAIL. Taken together, our study revealed that HSP27 phosphorylation modulates TRAIL-triggered activation of Src-Akt/ERK pro-survival signaling via interacting with β-arrestin2 in HeLa cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Anti-asialo GM1 antiserum treatment of lethally irradiated recipients before bone marrow transplantation: Evidence that recipient natural killer depletion enhances survival, engraftment, and hematopoietic recovery

International Nuclear Information System (INIS)

Tiberghien, P.; Longo, D.L.; Wine, J.W.; Alvord, W.G.; Reynolds, C.W.

1990-01-01

Natural killer (NK) cells are reported to have an important role in the resistance of lethally irradiated recipients to bone marrow transplantation (BMT). Therefore, we investigated the effects of recipient NK depletion on survival, chimerism, and hematopoietic reconstitution after lethal irradiation and the transplantation of limiting amounts of T-cell-deficient bone marrow (BM). When administered before BMT, anti-asialo GM1 (ASGM1) antiserum treatment, effective in depleting in vivo NK activity, was associated with a marked increase in survival in 3 of 3 allogeneic combinations (BALB/c into C3H/HeN, C57B1/6, or C3B6F1). This enhanced survival was independent of the susceptibility of each recipient strain to accept BALB/c BM. Moreover, recipient anti-ASGM1 treatment was also effective in increasing survival in recipients of syngeneic BM, suggesting that NK cells can adversely affect engraftment independent of genetically controlled polymorphic cell surface determinants. Analysis of chimerism in surviving animals 2 months post-BMT showed that recipient NK depletion significantly increased the level of donor engraftment when high doses of BM were transplanted. These studies also demonstrated that anti-ASGM1 pretreatment mainly resulted in an increase in extramedullary hematopoiesis in the second and third week after irradiation. Anti-ASGM1 treatment also dramatically accelerated the rate of appearance of donor-derived cells with a higher level of donor-cell engraftment apparent at a time when the differences in survival between NK-depleted and control BMT recipients became significant. Peripheral cell counts were also affected by NK depletion, with significantly enhanced platelet and red blood cell recovery and a moderate increase in granulocyte recovery

Anti-asialo GM1 antiserum treatment of lethally irradiated recipients before bone marrow transplantation: Evidence that recipient natural killer depletion enhances survival, engraftment, and hematopoietic recovery

Energy Technology Data Exchange (ETDEWEB)

Tiberghien, P.; Longo, D.L.; Wine, J.W.; Alvord, W.G.; Reynolds, C.W. (Program Resources, Inc., Frederick, MD (USA))

1990-10-01

Natural killer (NK) cells are reported to have an important role in the resistance of lethally irradiated recipients to bone marrow transplantation (BMT). Therefore, we investigated the effects of recipient NK depletion on survival, chimerism, and hematopoietic reconstitution after lethal irradiation and the transplantation of limiting amounts of T-cell-deficient bone marrow (BM). When administered before BMT, anti-asialo GM1 (ASGM1) antiserum treatment, effective in depleting in vivo NK activity, was associated with a marked increase in survival in 3 of 3 allogeneic combinations (BALB/c into C3H/HeN, C57B1/6, or C3B6F1). This enhanced survival was independent of the susceptibility of each recipient strain to accept BALB/c BM. Moreover, recipient anti-ASGM1 treatment was also effective in increasing survival in recipients of syngeneic BM, suggesting that NK cells can adversely affect engraftment independent of genetically controlled polymorphic cell surface determinants. Analysis of chimerism in surviving animals 2 months post-BMT showed that recipient NK depletion significantly increased the level of donor engraftment when high doses of BM were transplanted. These studies also demonstrated that anti-ASGM1 pretreatment mainly resulted in an increase in extramedullary hematopoiesis in the second and third week after irradiation. Anti-ASGM1 treatment also dramatically accelerated the rate of appearance of donor-derived cells with a higher level of donor-cell engraftment apparent at a time when the differences in survival between NK-depleted and control BMT recipients became significant. Peripheral cell counts were also affected by NK depletion, with significantly enhanced platelet and red blood cell recovery and a moderate increase in granulocyte recovery.

BAMBI Promotes C2C12 Myogenic Differentiation by Enhancing Wnt/β-Catenin Signaling

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Qiangling Zhang

2015-08-01

Full Text Available Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-β and enhances Wnt/β-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. In the current study, we found that the expression level of BAMBI peaked in the early differentiation phase of the C2C12 rodent myoblast cell line. Knockdown of BAMBI via siRNA inhibited C2C12 differentiation, indicated by repressed MyoD, MyoG, and MyHC expression as well as reductions in the differentiation and fusion indices. BAMBI knockdown reduced the activity of Wnt/β-catenin signaling, as characterized by the decreased nuclear translocation of β-catenin and the lowered transcription of Axin2, which is a well-documented target gene of the Wnt/β-catenin signaling pathway. Furthermore, treatment with LiCl, an activator of Wnt/β-catenin signaling, rescued the reduction in C2C12 differentiation caused by BAMBI siRNA. Taken together, our data suggest that BAMBI is required for normal C2C12 differentiation, and that its role in myogenesis is mediated by the Wnt/β-catenin pathway.

Kinesin Khc-73/KIF13B modulates retrograde BMP signaling by influencing endosomal dynamics at the Drosophila neuromuscular junction.

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Liao, Edward H; Gray, Lindsay; Tsurudome, Kazuya; El-Mounzer, Wassim; Elazzouzi, Fatima; Baim, Christopher; Farzin, Sarah; Calderon, Mario R; Kauwe, Grant; Haghighi, A Pejmun

2018-01-01

Retrograde signaling is essential for neuronal growth, function and survival; however, we know little about how signaling endosomes might be directed from synaptic terminals onto retrograde axonal pathways. We have identified Khc-73, a plus-end directed microtubule motor protein, as a regulator of sorting of endosomes in Drosophila larval motor neurons. The number of synaptic boutons and the amount of neurotransmitter release at the Khc-73 mutant larval neuromuscular junction (NMJ) are normal, but we find a significant decrease in the number of presynaptic release sites. This defect in Khc-73 mutant larvae can be genetically enhanced by a partial genetic loss of Bone Morphogenic Protein (BMP) signaling or suppressed by activation of BMP signaling in motoneurons. Consistently, activation of BMP signaling that normally enhances the accumulation of phosphorylated form of BMP transcription factor Mad in the nuclei, can be suppressed by genetic removal of Khc-73. Using a number of assays including live imaging in larval motor neurons, we show that loss of Khc-73 curbs the ability of retrograde-bound endosomes to leave the synaptic area and join the retrograde axonal pathway. Our findings identify Khc-73 as a regulator of endosomal traffic at the synapse and modulator of retrograde BMP signaling in motoneurons.

The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach.

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Sivina, Mariela; Kreitman, Robert J; Arons, Evgeny; Ravandi, Farhad; Burger, Jan A

2014-07-01

B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL. © 2014 John Wiley & Sons Ltd.

Adaptive memory: the survival scenario enhances item-specific processing relative to a moving scenario.

Science.gov (United States)

Burns, Daniel J; Hart, Joshua; Griffith, Samantha E; Burns, Amy D

2013-01-01

Nairne, Thompson, and Pandeirada (2007) found that retention of words rated for their relevance to survival is superior to that of words encoded under numerous other deep processing conditions. They suggested that our memory systems might have evolved to confer an advantage for survival-relevant information. Burns, Burns, and Hwang (2011) suggested a two-process explanation of the proximate mechanisms responsible for the survival advantage. Whereas most control tasks encourage only one type of processing, the survival task encourages both item-specific and relational processing. They found that when control tasks encouraged both types of processing, the survival processing advantage was eliminated. However, none of their control conditions included non-survival scenarios (e.g., moving, vacation, etc.), so it is not clear how this two-process explanation would explain the survival advantage when scenarios are used as control conditions. The present experiments replicated the finding that the survival scenario improves recall relative to a moving scenario in both a between-lists and within-list design and also provided evidence that this difference was accompanied by an item-specific processing difference, not a difference in relational processing. The implications of these results for several existing accounts of the survival processing effect are discussed.

Microwave assisted in situ synthesis of Ag–NaCMC films and their reproducible surface-enhanced Raman scattering signals

International Nuclear Information System (INIS)

Jiang, Tao; Li, Junpeng; Zhang, Li; Wang, Binbing; Zhou, Jun

2014-01-01

Graphical abstract: Two kinds of Ag–NaCMC films for surface-enhanced Raman scattering (SERS) were prepared by conventional heating and microwave assisted in situ reduction methods without any additional capping or reducing agents. A relatively narrow and symmetric surface plasmon resonance band was observed in the absorption spectra of the films fabricated by the microwave assisted in situ reduction method. More uniform silver nanoparticles (NPs) implied by the symmetric absorption spectrum were further confirmed by the scanning electron microscopy images. After the simulation of the E-field intensity distribution around the silver NPs in NaCMC film, the Raman scattering enhancement factors (EFs) of these films were then investigated with 4-mercaptobenzoic acid molecule as a SERS reporter. Improved reproducibility of SERS signal was obtained in the microwave assisted synthesized Ag–NaCMC film, although it maintained an EF as only 1.11 × 10 8 . The reproducible SERS signal of the Ag–NaCMC film is particularly attractive and this microwave assisted in situ reduction method is suitable for the production of excellent substrate for biosensor application. - Highlights: • The synthesis of Ag–NaCMC films was successfully fulfilled by a low-cost microwave method. • More uniform silver nanoparticles were observed in Ag–NaCMC film synthesized by microwave. • Improved reproducibility of SERS signal was obtained in microwave synthesized Ag–NaCMC film. - Abstract: Two kinds of Ag–NaCMC films for surface-enhanced Raman scattering (SERS) were prepared by conventional heating and microwave assisted in situ reduction methods without any additional capping or reducing agents. A relatively narrow and symmetric surface plasmon resonance band was observed in the absorption spectra of the films fabricated by the microwave assisted in situ reduction method. More uniform silver nanoparticles (NPs) implied by the symmetric absorption spectrum were further confirmed by

Protein kinase D1 stimulates proliferation and enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-dependent signaling pathway

International Nuclear Information System (INIS)

Karam, Manale; Legay, Christine; Auclair, Christian; Ricort, Jean-Marc

2012-01-01

Protein kinase D1, PKD1, is a novel serine/threonine kinase whose altered expression and dysregulation in many tumors as well as its activation by several mitogens suggest that this protein could regulate proliferation and tumorigenesis. Nevertheless, the precise signaling pathways used are still unclear and the potential direct role of PKD1 in tumor development and progression has not been yet investigated. In order to clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the effects of PKD1 overexpression in a human adenocarcinoma breast cancer cell line, MCF-7 cells. We demonstrated that overexpression of PKD1 specifically promotes MCF-7 cell proliferation through accelerating G0/G1 to S phase transition of the cell cycle. Moreover, inhibition of endogenous PKD1 significantly reduced cell proliferation. Taken together, these results clearly strengthen the regulatory role of PKD1 in cell growth. We also demonstrated that overexpression of PKD1 specifically diminished serum- and anchorage-dependence for proliferation and survival in vitro and allowed MCF-7 cells to form tumors in vivo. Thus, all these data highlight the central role of PKD1 in biological processes which are hallmarks of malignant transformation. Analysis of two major signaling pathways implicated in MCF-7 cell proliferation showed that PKD1 overexpression significantly increased ERK1/2 phosphorylation state without affecting Akt phosphorylation. Moreover, PKD1 overexpression-stimulated cell proliferation and anchorage-independent growth were totally impaired by inhibition of the MEK/ERK kinase cascade. However, neither of these effects was affected by blocking the PI 3-kinase/Akt signaling pathway. Thus, the MEK/ERK signaling appears to be a determining pathway mediating the biological effects of PKD1 in MCF-7 cells. Taken together, all these data demonstrate that PKD1 overexpression increases the aggressiveness of MCF-7 breast cancer cells through enhancing their oncogenic

Nanopolyaniline as immobilization template for signal enhancement of surface plasmon resonance biosensor - A preliminary study

Science.gov (United States)

Kamarun, Dzaraini; Abdul Azem, Nor Hazirah Kamel; Sarijo, Siti Halimah; Mohd, Ahmad Faiza; Abdullah @ Mohd Noor, Mashita

2012-07-01

A technique for the enhancement of Surface Plasmon Resonance (SPR) signal for sensing biomolecular interactions is described. Polyaniline (PANI) of particle size in the range of 1 to 15 nm was synthesized and used as the template for the immobilization of protein molecules. Biomolecular interactions of unbound and PANI-bound proteins with antibody molecules were SPR-monitored using a model system comprising of Bovine Serum Albumin (BSA) and anti BSA. A 7-fold increased in the signal was recorded from interactions of the PANI-bound BSA with anti BSA compared to the interactions of its unbound counterpart. This preliminary observation provides new avenue in immunosensor technology for improving the detection sensitivity of SPR biosensor; and thereby increasing the lower detection limit of biomolecules.

Enhanced left ventricular mass regression after aortic valve replacement in patients with aortic stenosis is associated with improved long-term survival.

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Ali, Ayyaz; Patel, Amit; Ali, Ziad; Abu-Omar, Yasir; Saeed, Amber; Athanasiou, Thanos; Pepper, John

2011-08-01

Aortic valve replacement in patients with aortic stenosis is usually followed by regression of left ventricular hypertrophy. More complete resolution of left ventricular hypertrophy is suggested to be associated with superior clinical outcomes; however, its translational impact on long-term survival after aortic valve replacement has not been investigated. Demographic, operative, and clinical data were obtained retrospectively through case note review. Transthoracic echocardiography was used to measure left ventricular mass preoperatively and at annual follow-up visits. Patients were classified according to their reduction in left ventricular mass at 1 year after the operation: group 1, less than 25 g; group 2, 25 to 150 g; and group 3, more than 150 g. Kaplan-Meier and multivariable Cox regression were used. A total of 147 patients were discharged from the hospital after aortic valve replacement for aortic stenosis between 1991 and 2001. Preoperative left ventricular mass was 279 ± 98 g in group 1 (n = 47), 347 ± 104 g in group 2 (n = 62), and 491 ± 183 g in group 3 (n = 38) (P regression such as ischemic heart disease or hypertension, valve type, or valve size used. Ten-year actuarial survival was not statistically different in patients with enhanced left ventricular mass regression when compared with the log-rank test (group 1, 51% ± 9%; group 2, 54% ± 8%; and group 3, 72% ± 10%) (P = .26). After adjustment, left ventricular mass reduction of more than 150 g was demonstrated as an independent predictor of improved long-term survival on multivariate analysis (P = .02). Our study is the first to suggest that enhanced postoperative left ventricular mass regression, specifically in patients undergoing aortic valve replacement for aortic stenosis, may be associated with improved long-term survival. In view of these findings, strategies purported to be associated with superior left ventricular mass regression should be considered when undertaking

The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway.

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Wang, Songbo; Wang, Guoqing; Zhang, Mengyuan; Zhuang, Lu; Wan, Xiaojuan; Xu, Jingren; Wang, Lina; Zhu, Xiaotong; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Shu, Gang; Jiang, Qingyan

2016-11-15

It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway. Copyright © 2016. Published by Elsevier Ireland Ltd.

Heat-killed Lactobacillus spp. cells enhance survivals of Caenorhabditis elegans against Salmonella and Yersinia infections.

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Lee, J; Choe, J; Kim, J; Oh, S; Park, S; Kim, S; Kim, Y

2015-12-01

This study examined the effect of feeding heat-killed Lactobacillus cells on the survival of Caenorhabditis elegans nematodes after Salmonella Typhimurium and Yersinia enterocolitica infection. The feeding of heat-killed Lactobacillus plantarum 133 (LP133) and Lactobacillus fermentum 21 (LP21) cells to nematodes was shown to significantly increase the survival rate as well as stimulate the expression of pmk-1 gene that key factor for C. elegans immunity upon infection compared with control nematodes that were only fed Escherichia coli OP50 (OP50) cells. These results suggest that heat-killed LP133 and LF21 cells exert preventive or protective effects against the Gram-negative bacteria Salm. Typhimurium and Y. enterocolitica. To better understand the mechanisms underlying the LF21-mediated and LP133-mediated protection against bacterial infection in nematodes, transcriptional profiling was performed for each experimental group. These experiments showed that genes related to energy generation and ageing, regulators of insulin/IGF-1-like signalling, DAF genes, oxidation and reduction processes, the defence response and/or the innate immune response, and neurological processes were upregulated in nematodes that had been fed heat-killed Lactobacillus cells compared with nematodes that had been fed E. coli cells. In this study, the feeding of heat-killed Lactobacillus bacteria to Caenorhabditis elegans nematodes was shown to decrease infection by Gram-negative bacteria and increase the host lifespan. C. elegans has a small, well-organized genome and is an excellent in vivo model organism; thus, these results will potentially shed light on important Lactobacillus-host interactions. © 2015 The Society for Applied Microbiology.

Inhibition of WNT signaling reduces differentiation and induces sensitivity to doxorubicin in human malignant neuroblastoma SH-SY5Y cells.

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Suebsoonthron, Junjira; Jaroonwitchawan, Thiranut; Yamabhai, Montarop; Noisa, Parinya

2017-06-01

Neuroblastoma is one of the most common cancers in infancy, arising from the neuroblasts during embryonic development. This cancer is difficult to treat and resistance to chemotherapy is often found; therefore, clinical trials of novel therapeutic approaches, such as targeted-cancer signaling, could be an alternative for a better treatment. WNT signaling plays significant roles in the survival, proliferation, and differentiation of human neuroblastoma. In this report, WNT signaling of a malignant human neuroblastoma cell line, SH-SY5Y cells, was inhibited by XAV939, a specific inhibitor of the Tankyrase enzyme. XAV939 treatment led to the reduction of β-catenin within the cells, confirming its inhibitory effect of WNT. The inhibition of WNT signaling by XAV939 did not affect cell morphology, survival, and proliferation; however, the differentiation and sensitivity to anticancer drugs of human neuroblastoma cells were altered. The treatment of XAV939 resulted in the downregulation of mature neuronal markers, including β-tubulin III, PHOX2A, and PHOX2B, whereas neural progenitor markers (PAX6, TFAP2α, and SLUG) were upregulated. In addition, the combination of XAV939 significantly enhanced the sensitivity of SH-SY5Y and IMR-32 cells to doxorubicin in both 2D and 3D culture systems. Microarray gene expression profiling suggested numbers of candidate target genes of WNT inhibition by XAV939, in particular, p21, p53, ubiquitin C, ZBED8, MDM2, CASP3, and FZD1, and this explained the enhanced sensitivity of SH-SY5Y cells to doxorubicin. Altogether, these results proposed that the altered differentiation of human malignant neuroblastoma cells by inhibiting WNT signaling sensitized the cells to anticancer drugs. This approach could thus serve as an effective treatment option for aggressive brain malignancy.

How can survival processing improve memory encoding?

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Luo, Meng; Geng, Haiyan

2013-11-01

We investigated the psychological mechanism of survival processing advantage from the perspective of false memory in two experiments. Using a DRM paradigm in combination with analysis based on signal detection theory, we were able to separately examine participants' utilization of verbatim representation and gist representation. Specifically, in Experiment 1, participants rated semantically related words in a survival scenario for a survival condition but rated pleasantness of words in the same DRM lists for a non-survival control condition. The results showed that participants demonstrated more gist processing in the survival condition than in the pleasantness condition; however, the degree of item-specific processing in the two encoding conditions did not significantly differ. In Experiment 2, the control task was changed to a category rating task, in which participants were asked to make category ratings of words in the category lists. We found that the survival condition involved more item-specific processing than did the category condition, but we found no significant difference between the two encoding conditions at the level of gist processing. Overall, our study demonstrates that survival processing can simultaneously promote gist and item-specific representations. When the control tasks only promoted either item-specific representation or gist representation, memory advantages of survival processing occurred.

Consequences of a dark disk for the Fermi and PAMELA signals in theories with a Sommerfeld enhancement

International Nuclear Information System (INIS)

Cholis, Ilias; Goodenough, Lisa

2010-01-01

Much attention has been given to dark matter explanations of the PAMELA positron fraction and Fermi electronic excesses. For those theories with a TeV-scale WIMP annihilating through a light force-carrier, the associated Sommerfeld enhancement provides a natural explanation of the large boost factor needed to explain the signals, and the light force-carrier naturally gives rise to hard cosmic ray spectra without excess π 0 -gamma rays or anti-protons. The Sommerfeld enhancement of the annihilation rate, which at low relative velocities v rel scales as 1/v rel , relies on the comparatively low velocity dispersion of the dark matter particles in the smooth halo. Dark matter substructures in which the velocity dispersion is smaller than in the smooth halo have even larger annihilation rates. N-body simulations containing only dark matter predict the existence of such structures, for example subhalos and caustics, and the effects of these substructures on dark matter indirect detection signals have been studied extensively. The addition of baryons into cosmological simulations of disk-dominated galaxies gives rise to an additional substructure component, a dark disk. The disk has a lower velocity dispersion than the spherical halo component by a factor ∼ 6, so the contributions to dark matter signals from the disk can be more significant in Sommerfeld models than for WIMPs without such low-velocity ehancements. We consider the consequences of a dark disk on the observed signals of e + e − , p p-bar and γ-rays as measured by Fermi and PAMELA in models where the WIMP annihilations are into a light boson. We find that both the PAMELA and Fermi results are easily accomodated by scenarios in which a disk signal is included with the standard spherical halo signal. If contributions from the dark disk are important, limits from extrapolations to the center of the galaxy contain significant uncertainties beyond those from the spherical halo profile alone

Corals like it waxed: paraffin-based antifouling technology enhances coral spat survival.

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Jan Tebben

Full Text Available The early post-settlement stage is the most sensitive during the life history of reef building corals. However, few studies have examined the factors that influence coral mortality during this period. Here, the impact of fouling on the survival of newly settled coral spat of Acropora millepora was investigated by manipulating the extent of fouling cover on settlement tiles using non-toxic, wax antifouling coatings. Survival of spat on coated tiles was double that on control tiles. Moreover, there was a significant negative correlation between percentage cover of fouling and spat survival across all tiles types, suggesting that fouling in direct proximity to settled corals has detrimental effects on early post-settlement survival. While previous studies have shown that increased fouling negatively affects coral larval settlement and health of juvenile and adult corals, to the best of our knowledge, this is the first study to show a direct relationship between fouling and early post-settlement survival for a broadcast spawning scleractinian coral. The negative effects of fouling on this sensitive life history stage may become more pronounced in the future as coastal eutrophication increases. Our results further suggest that targeted seeding of coral spat on artificial surfaces in combination with fouling control could prove useful to improve the efficiency of sexual reproduction-based coral propagation for reef rehabilitation.

Enhanced signal dispersion in saturation transfer difference experiments by conversion to a 1D-STD-homodecoupled spectrum

Energy Technology Data Exchange (ETDEWEB)

Martin-Pastor, Manuel; Vega-Vazquez, Marino [Universidade de Santiago de Compostela, Laboratorio Integral de Dinamica e Estructura de Biomoleculas Jose R. Carracido, Unidade de Resonancia Magnetica, Edificio CACTUS, RIAIDT (Spain); Capua, Antonia De [Seconda Universita degli Studi di Napoli, Dipartimento di Scienze Ambientali (Italy); Canales, Angeles [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y funcion de proteinas (Spain); Andre, Sabine; Gabius, Hans-Joachim [Ludwig-Maximilians-Universitaet, Institut fuer Physiologische Chemie, Tieraerztliche Fakultaet (Germany); Jimenez-Barbero, Jesus [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y funcion de proteinas (Spain)], E-mail: JJbarbero@cib.csic.es

2006-10-15

The saturation transfer difference (STD) experiment is a rich source of information on topological aspects of ligand binding to a receptor. The epitope mapping is based on a magnetization transfer after signal saturation from the receptor to the ligand, where interproton distances permit this process. Signal overlap in the STD spectrum can cause difficulties to correctly assign and/or quantitate the measured enhancements. To address this issue we report here a modified version of the routine experiment and a processing scheme that provides a 1D-STD homodecoupled spectrum (i.e. an experiment in which all STD signals appear as singlets) with line widths similar to those in original STD spectrum. These refinements contribute to alleviate problems of signal overlap. The experiment is based on 2D-J-resolved spectroscopy, one of the fastest 2D experiments under conventional data sampling in the indirect dimension, and provides excellent sensitivity, a key factor for the difference experiments.

LEF-1 and TCF4 expression correlate inversely with survival in colorectal cancer

Directory of Open Access Journals (Sweden)

Kirchner Thomas

2010-11-01

Full Text Available Abstract Background Most colorectal carcinomas are driven by an activation of the canonical Wnt signalling pathway, which promotes the expression of multiple target genes mediating proliferation inavasion and invasion. Upon activation of the Wnt signalling pathway its key player β-catenin translocates from the cytoplasm to the nucleus and binds to members of the T-cell factor (TCF/lymphoid enhancer factor (LEF-1 family namely LEF-1 and TCF4 which are central mediators of transcription. In this study we investigated the expression of β-Catenin, LEF1 and TCF4 in colorectal carcinomas and their prognostic significance. Methods Immunohistochemical analyses of LEF-1, TCF4 and nuclear β-Catenin were done using a tissue microarray with 214 colorectal cancer specimens. The expression patterns were compared with each other and the results were correlated with clinicopathologic variables and overall survival in univariate and multivariate analysis. Results LEF-1 expression was found in 56 (26% and TCF4 expression in 99 (46% of colorectal carcinomas and both were heterogenously distributed throughout the tumours. Comparing LEF-1, TCF4 and β-catenin expression patterns we found no correlation. In univariate analysis, TCF4 expression turned out to be a negative prognostic factor being associated with shorter overall survival (p = 0.020, whereas LEF-1 expression as well as a LEF-1/TCF4 ratio were positive prognostic factors and correlated with longer overall survival (p = 0.015 respectively p = 0.001. In multivariate analysis, LEF-1 and TCF4 expression were confirmed to be independent predictors of longer respectively shorter overall survival, when considered together with tumour stage, gender and age (risk ratio for LEF-1: 2.66; p = 0.027 risk ratio for TCF4: 2.18; p = 0.014. Conclusions This study demonstrates different prognostic values of LEF-1 and TCF4 expression in colorectal cancer patients indicating different regulation of these transcription

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

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Kandasamy, Neelamegam; Ashokkumar, Natarajan, E-mail: npashokkumar1@gmail.com

2014-09-01

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

International Nuclear Information System (INIS)

Kandasamy, Neelamegam; Ashokkumar, Natarajan

2014-01-01

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

E1(-)E4(+) adenoviral gene transfer vectors function as a "pro-life" signal to promote survival of primary human endothelial cells.

Science.gov (United States)

Ramalingam, R; Rafii, S; Worgall, S; Brough, D E; Crystal, R G

1999-05-01

Although endothelial cells are quiescent and long-lived in vivo, when they are removed from blood vessels and cultured in vitro they die within days to weeks. In studies of the interaction of E1(-)E4(+) replication-deficient adenovirus (Ad) vectors and human endothelium, the cells remained quiescent and were viable for prolonged periods. Evaluation of these cultures showed that E1(-)E4(+) Ad vectors provide an "antiapoptotic" signal that, in association with an increase in the ratio of Bcl2 to Bax levels, induces the endothelial cells to enter a state of "suspended animation," remaining viable for at least 30 days, even in the absence of serum and growth factors. Although the mechanisms initiating these events are unclear, the antiapoptoic signal requires the presence of E4 genes in the vector genome, suggesting that one or more E4 open reading frames of subgroup C Ad initiate a "pro-life" program that modifies cultured endothelial cells to survive for prolonged periods.

Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma.

Science.gov (United States)

Liu, W Robert; Shipp, Margaret A

2017-11-23

Classical Hodgkin lymphoma (cHL) is an unusual B-cell-derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number-dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor-positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade. © 2017 by The American Society of Hematology.

Investigations into the bystander effect: signal versus response

International Nuclear Information System (INIS)

Vines, A.M.; Seymour, C.B.; Mothersill, C.E.

2003-01-01

The bystander effect is the general term used to describe the effects seen in cells or tissue that have never been directly irradiated, but display similar symptoms to those that have. Some of these symptoms include reduced cell survival, chromosomal aberrations, and increased apoptosis. This investigation aims to explore the signal produced by certain cell and tissue types, and the relationship this has with the subsequent response. The goal is to elucidate whether the reduction in cell survival frequently seen in response to the bystander effect is determined by the signal produced or the response of the cell type. Firstly, a matrix design experiment was set up using 3 cell lines. Each cell line was irradiated to produce ICCM (Irradiated Cell Conditioned Medium), which was in turn used to treat all cell lines in the study. Medium transfer is carried out within cell lines, (ICCM from CHO onto CHO cells) and between cell lines (ICCM from CHO onto HPV-G cells). In the second set of experiments, tissue samples from male Wister rats were used to generate ITCM (Irradiated Tissue Conditioned Medium). This medium was then tested on a cell line with an established response to the bystander effect. As an extension to these two experimental protocols, both ICCM and ITCM were used to investigate if there is calcium flux in the cells as a response to the bystander medium. This has recently been shown to be an early response to the bystander signal. Results indicate that it is the signal produced by the irradiated cells that determine the overall effect of the bystander signal, and not the response of the cells expose to it. CHO-K1 cells treated with autologous ICCM show a 16.2% drop in cell survival. However, when this cell line is treated with HPV-G ICCM, it shows a 36.5% drop in survival. HPV-G cells treated with autologous medium display a similar response to this, with a 41.1% drop in survival, though when treated with CHO-K1 ICCM, the drop in survival is 22.9%. This

Indian hedgehog signaling triggers Nkx3.2 protein degradation during chondrocyte maturation

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Choi, Seung-Won; Jeong, Da-Un; Kim, Jeong-Ah; Lee, Boyoung; Joeng, Kyu Sang; Long, Fanxin; Kim, Dae-Won

2015-01-01

The Indian hedgehog (Ihh) pathway plays an essential role in facilitating chondrocyte hypertrophy and bone formation during skeletal development. Nkx3.2 is initially induced in chondrocyte precursor cells, maintained in early-stage chondrocytes, and down-regulated in terminal-stage chondrocytes. Consistent with these expression patterns, Nkx3.2 has been shown to enhance chondrocyte differentiation and cell survival, while inhibiting chondrocyte hypertrophy and apoptosis. Thus, in this work, we investigate whether Nkx3.2, an early stage chondrogenic factor, can be regulated by Ihh, a key regulator for chondrocyte hypertrophy. Here, we show that Ihh signaling can induce proteasomal degradation of Nkx3.2. In addition, we found that Ihh can suppress levels of Lrp (Wnt co-receptor) and Sfrp (Wnt antagonist) expression, which, in turn, may selectively enhance Lrp-independent non-canonical Wnt pathways in chondrocyte. In agreement with these findings, Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation. Finally, we found that Nkx3.2 protein levels in chondrocytes are remarkably elevated in mice defective in Ihh signaling by deletion of either Ihh or Smoothened. Thus, these results suggest that Ihh/Wnt5a signaling may play a role in negative regulation of Nkx3.2 for appropriate progression of chondrocyte hypertrophy during chondrogenesis. PMID:22507129

Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway

International Nuclear Information System (INIS)

Tseng, Ya-Shih; Lee, Jenq-Chang; Huang, Chi-Ying F; Liu, Hsiao-Sheng

2009-01-01

Overexpression of Aurora-A and mutant Ras (Ras V12 ) together has been detected in human bladder cancer tissue. However, it is not clear whether this phenomenon is a general event or not. Although crosstalk between Aurora-A and Ras signaling pathways has been reported, the role of these two genes acting together in tumorigenesis remains unclear. Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-ras mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either Ras V12 and wild-type Aurora-A (designated WT) or Ras V12 and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved. Overexpression of wild-type Aurora-A and mutation of Ras V12 were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the Ras V12 transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the Ras V12 transformants. Wild-type-Aurora-A enhances focus formation and aggregation of the Ras V12 transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway

Differences in Signal Intensity and Enhancement on MR Images of the Perivascular Spaces in the Basal Ganglia versus Those in White Matter.

Science.gov (United States)

Naganawa, Shinji; Nakane, Toshiki; Kawai, Hisashi; Taoka, Toshiaki

2018-01-18

To elucidate differences between the perivascular space (PVS) in the basal ganglia (BG) versus that found in white matter (WM) using heavily T 2 -weighted FLAIR (hT 2 -FL) in terms of 1) signal intensity on non-contrast enhanced images, and 2) the degree of contrast enhancement by intravenous single dose administration of gadolinium based contrast agent (IV-SD-GBCA). Eight healthy men and 13 patients with suspected endolymphatic hydrops were included. No subjects had renal insufficiency. All subjects received IV-SD-GBCA. MR cisternography (MRC) and hT 2 -FL images were obtained prior to and 4 h after IV-SD-GBCA. The signal intensity of the PVS in the BG, subinsular WM, and the cerebrospinal fluid (CSF) in Ambient cistern (CSF AC ) and CSF in Sylvian fissure (CSF Syl ) was measured as well as that of the thalamus. The signal intensity ratio (SIR) was calculated by dividing the intensity by that of the thalamus. We used 5% as a threshold to determine the significance of the statistical test. In the pre-contrast scan, the SIR of the PVS in WM (Mean ± standard deviation, 1.83 ± 0.46) was significantly higher than that of the PVS in the BG (1.05 ± 0.154), CSF Syl (1.03 ± 0.15) and the CSF AC (0.97 ± 0.29). There was no significant difference between the SIR of the PVS in the BG compared to the CSF AC and CSF Syl . For the evaluation of the contrast enhancement effect, significant enhancement was observed in the PVS in the BG, the CSF AC and the CSF Syl compared to the pre-contrast scan. No significant contrast enhancement was observed in the PVS in WM. The signal intensity difference between the PVS in the BG versus WM on pre-contrast images suggests that the fluid composition might be different between these PVSs. The difference in the contrast enhancement between the PVSs in the BG versus WM suggests a difference in drainage function.

Activation of Gαq Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

Science.gov (United States)

Arey, Rachel N; Stein, Geneva M; Kaletsky, Rachel; Kauffman, Amanda; Murphy, Coleen T

2018-05-02

Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G αq signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced G αq signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G αq specifically in aged animals rescues the ability to form memory. Activation of G αq in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity. Copyright © 2018 Elsevier Inc. All rights reserved.

Different Signal Enhancement Pathways of Attention and Consciousness Underlie Perception in Humans.

Science.gov (United States)

van Boxtel, Jeroen J A

2017-06-14

It is not yet known whether attention and consciousness operate through similar or largely different mechanisms. Visual processing mechanisms are routinely characterized by measuring contrast response functions (CRFs). In this report, behavioral CRFs were obtained in humans (both males and females) by measuring afterimage durations over the entire range of inducer stimulus contrasts to reveal visual mechanisms behind attention and consciousness. Deviations relative to the standard CRF, i.e., gain functions, describe the strength of signal enhancement, which were assessed for both changes due to attentional task and conscious perception. It was found that attention displayed a response-gain function, whereas consciousness displayed a contrast-gain function. Through model comparisons, which only included contrast-gain modulations, both contrast-gain and response-gain effects can be explained with a two-level normalization model, in which consciousness affects only the first level and attention affects only the second level. These results demonstrate that attention and consciousness can effectively show different gain functions because they operate through different signal enhancement mechanisms. SIGNIFICANCE STATEMENT The relationship between attention and consciousness is still debated. Mapping contrast response functions (CRFs) has allowed (neuro)scientists to gain important insights into the mechanistic underpinnings of visual processing. Here, the influence of both attention and consciousness on these functions were measured and they displayed a strong dissociation. First, attention lowered CRFs, whereas consciousness raised them. Second, attention manifests itself as a response-gain function, whereas consciousness manifests itself as a contrast-gain function. Extensive model comparisons show that these results are best explained in a two-level normalization model in which consciousness affects only the first level, whereas attention affects only the second level

Cellular stress-induced up-regulation of FMRP promotes cell survival by modulating PI3K-Akt phosphorylation cascades

Directory of Open Access Journals (Sweden)

Wells David

2011-02-01

Full Text Available Abstract Background Fragile X syndrome (FXS, the most commonly inherited mental retardation and single gene cause of autistic spectrum disorder, occurs when the Fmr1 gene is mutated. The product of Fmr1, fragile X linked mental retardation protein (FMRP is widely expressed in HeLa cells, however the roles of FMRP within HeLa cells were not elucidated, yet. Interacting with a diverse range of mRNAs related to cellular survival regulatory signals, understanding the functions of FMRP in cellular context would provide better insights into the role of this interesting protein in FXS. Using HeLa cells treated with etoposide as a model, we tried to determine whether FMRP could play a role in cell survival. Methods Apoptotic cell death was induced by etoposide treatment on Hela cells. After we transiently modulated FMRP expression (silencing or enhancing by using molecular biotechnological methods such as small hairpin RNA virus-induced knock down and overexpression using transfection with FMRP expression vectors, cellular viability was measured using propidium iodide staining, TUNEL staining, and FACS analysis along with the level of activation of PI3K-Akt pathway by Western blot. Expression level of FMRP and apoptotic regulator BcL-xL was analyzed by Western blot, RT-PCR and immunocytochemistry. Results An increased FMRP expression was measured in etoposide-treated HeLa cells, which was induced by PI3K-Akt activation. Without FMRP expression, cellular defence mechanism via PI3K-Akt-Bcl-xL was weakened and resulted in an augmented cell death by etoposide. In addition, FMRP over-expression lead to the activation of PI3K-Akt signalling pathway as well as increased FMRP and BcL-xL expression, which culminates with the increased cell survival in etoposide-treated HeLa cells. Conclusions Taken together, these results suggest that FMRP expression is an essential part of cellular survival mechanisms through the modulation of PI3K, Akt, and Bcl-xL signal

Maximizing survivability of acyclic transmission networks with multi-state retransmitters and vulnerable nodes

International Nuclear Information System (INIS)

Levitin, Gregory

2002-01-01

In this paper, an algorithm for optimal allocation of multi-state elements (MEs) in acyclic transmission networks (ATNs) with vulnerable nodes is suggested. The ATNs consist of a number of positions (nodes) in which MEs capable of receiving and sending a signal are allocated. Each network has a root position where the signal source is located, a number of leaf positions that can only receive a signal, and a number of intermediate positions containing MEs capable of transmitting the received signal to some other nodes. Each ME that is located in a nonleaf node can have different states determined by a set of nodes receiving the signal directly from this ME. The probability of each state is assumed to be known for each ME. Each ATN node with all the MEs allocated at this node can be destroyed by external impact (common cause failure) with a given probability. The ATN survivability is defined as the probability that a signal from the root node is transmitted to each leaf node. The optimal distribution of MEs with different characteristics among ATN positions provides the greatest possible ATN survivability. It is shown that the node vulnerability index affects the optimal distribution. The suggested algorithm is based on using a universal generating function technique for network survivability evaluation. A genetic algorithm is used as the optimization tool. Illustrative examples are presented

Enhanced signaling scheme with admission control in the hybrid optical wireless (HOW) networks

DEFF Research Database (Denmark)

Yan, Ying; Yu, Hao; Wessing, Henrik

2009-01-01

that it can support stringent Quality of Service (QoS) requirements. In this paper, we describe and evaluate a resource management framework designed for the HOW networks. There are two parts in the resource management framework The first part is the Enhanced MPCP (E-MPCP) scheme aiming at improving signaling...... dropping probability depend on several factors. These factors include the frame duration, the traffic load and the total number of shared users. The results also highlight that our proposed system achieves significant improvements over the traditional approach in terms of user QoS guarantee and network...

A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

Directory of Open Access Journals (Sweden)

Pluchino Stefano

2011-07-01

Full Text Available Abstract Background Dopamine-synthesizing (dopaminergic, DA neurons in the ventral midbrain (VM constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+ neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd

MR imaging of renal cell carcinoma: associations among signal intensity, tumor enhancement, and pathologic findings.

OpenAIRE

Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio

2003-01-01

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics ...

Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.

Science.gov (United States)

Tartaglia, Marco; Gelb, Bruce D

2010-12-01

RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. © 2010 New York Academy of Sciences.

The n-butanolic extract of Opuntia ficus-indica var. saboten enhances long-term memory in the passive avoidance task in mice.

Science.gov (United States)

Kim, Jong Min; Kim, Dong Hyun; Park, Se Jin; Park, Dong Hyun; Jung, Seo Yun; Kim, Hyoung Ja; Lee, Yong Sup; Jin, Changbae; Ryu, Jong Hoon

2010-08-16

Opuntia ficus-indica var. saboten Makino (Cactaceae) is used to treat burns, edema, dyspepsia, and asthma in traditional medicine. The present study investigated the beneficial effects of the n-butanolic extract of O. ficus-indica var. saboten (BOF) on memory performance in mice and attempts to uncover the mechanisms underlying its action. Memory performance was assessed with the passive avoidance task, and western blotting and immunohistochemistry were used to measure changes in protein expression and cell survival. After the oral administration of BOF for 7 days, the latency time in the passive avoidance task was significantly increased relative to vehicle-treated controls (P<0.05). Western blotting revealed that the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding-protein (pCREB), and phosphorylated extracellular signal-regulated kinase (pERK) 1/2 were significantly increased in hippocampal tissue after 7 days of BOF administration (P<0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining also revealed that BOF significantly enhanced the survival of immature neurons, but did not affect neuronal cell proliferation in the subgranular zone of the hippocampal dentate gyrus. These results suggest that the subchronic administration of BOF enhances long-term memory, and that this effect is partially mediated by ERK-CREB-BDNF signaling and the survival of immature neurons. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis.

Science.gov (United States)

Kwon, Young-Chan; Sasaki, Reina; Meyer, Keith; Ray, Ranjit

2017-11-01

Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from in vitro analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein. IMPORTANCE Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that

Differentiation of mass-forming focal pancreatitis from pancreatic ductal adenocarcinoma: value of characterizing dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity color mapping

Energy Technology Data Exchange (ETDEWEB)

Kim, Mimi [Hanyang University College of Medicine, Department of Radiology, Hanyang Medical Center, Seoul (Korea, Republic of); Jang, Kyung Mi [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jae-Hun; Jeong, Woo Kyoung; Kim, Seong Hyun; Kang, Tae Wook; Kim, Young Kon; Cha, Dong Ik [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Kyunga [Samsung Medical Center, Biostatics and Clinical Epidemiology Center, Research Institute for Future Medicine, Seoul (Korea, Republic of)

2017-04-15

To evaluate the value of dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity colour mapping (SICM) to differentiate mass-forming focal pancreatitis (MFFP) from pancreatic ductal adenocarcinoma (PDAC). Forty-one clinicopathologically proven MFFPs and 144 surgically confirmed PDACs were enrolled. Laboratory and MR imaging parameters were used to differentiate MFFP from PDAC. In particular, enhancement patterns on MR images adding SICM were evaluated. By using classification tree analysis (CTA), we determined the predictors for the differentiation of MFFP from PDAC. In the CTA, with all parameters except enhancement pattern on SICM images, ductal obstruction grade and T1 hypointensity grade of the pancreatic lesion were the first and second splitting predictor for differentiation of MFFP from PDAC, in order. By adding an enhancement pattern on the SICM images to CTA, the enhancement pattern was the only splitting predictor to differentiate MFFP from PDAC. The CTA model including enhancement pattern on SICM images has sensitivity of 78.0 %, specificity of 99.3 %, and accuracy of 94.6 % for differentiating MFFP from PDAC. The characterization of enhancement pattern for pancreatic lesions on contrast-enhanced MR images adding SICM would be helpful to differentiate MFFP from PDAC. (orig.)

Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

Science.gov (United States)

Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

2016-09-01

Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. Copyright © 2016 Elsevier Inc. All rights reserved.

BNCT of intracerebral melanoma. Enhanced survival and cure following Cereport mediated opening of the blood-brain barrier

International Nuclear Information System (INIS)

Barth, R.F.; Yang, W.; Bartus, R.T.; Rotaru, J.H.; Ferketich, A.K.; Moeschberger, M.L.; Nawrocky, M.M.; Coderre, J.A.

2000-01-01

Cereport is a bradykinin analogue that produces a transient, pharmacologically mediated opening of the blood-brain barrier (BBB). The present study was designed to determine if Cereport could enhance the delivery of BPA and the efficacy of BNCT in nude rats bearing intracerebral implants of the human MRA 27 melanoma. Animals that received intracarotid (i.c.) injection of Cereport and i.c. BPA had a mean survival time of 115 d compared to 82 d without Cereport, 42 d for i.v. BPA with Cereport and 31 d for irradiated controls. The combination of i.c. Cereport and BPA produced a 400% increase in the life span with 35% long-term survivors (>180 d). (author)

Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats.

Directory of Open Access Journals (Sweden)

Tiffany N Eady

Full Text Available Docosahexaenoic acid, a major omega-3 essential fatty acid family member, improves behavioral deficit and reduces infarct volume and edema after experimental focal cerebral ischemia. We hypothesize that DHA elicits neuroprotection by inducing AKT/p70S6K phosphorylation, which in turn leads to cell survival and protects against ischemic stroke in young and aged rats.Rats underwent 2 h of middle cerebral artery occlusion (MCAo. DHA, neuroprotectin D1 (NPD1 or vehicle (saline was administered 3 h after onset of stroke. Neurological function was evaluated on days 1, 2, 3, and 7. DHA treatment improved functional recovery and reduced cortical, subcortical and total infarct volumes 7 days after stroke. DHA also reduced microglia infiltration and increased the number of astrocytes and neurons when compared to vehicle on days 1 and 7. Increases in p473 AKT and p308 AKT phosphorylation/activation were observed in animals treated with DHA 4 h after MCAo. Activation of other members of the AKT signaling pathway were also observed in DHA treated animals including increases in pS6 at 4 h and pGSK at 24 h. DHA or NPD1 remarkably reduced total and cortical infarct in aged rats. Moreover, we show that in young and aged rats DHA treatment after MCAo potentiates NPD1 biosynthesis. The phosphorylation of p308 AKT or pGSK was not different between groups in aged rats. However, pS6 expression was increased with DHA or NPD1 treatment when compared to vehicle.We suggest that DHA induces cell survival, modulates the neuroinflammatory response and triggers long term restoration of synaptic circuits. Both DHA and NPD1 elicited remarkable protection in aged animals. Accordingly, activation of DHA signaling might provide benefits in the management of ischemic stroke both acutely as well as long term to limit ensuing disabilities.

PG545, a heparan sulfate mimetic, reduces heparanase expression in vivo, blocks spontaneous metastases and enhances overall survival in the 4T1 breast carcinoma model.

Directory of Open Access Journals (Sweden)

Edward Hammond

Full Text Available PG545 is a clinically relevant heparan sulfate (HS mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase - the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications. Recent concerns raised about the paucity of overall survival as an endpoint in mouse models of clinically relevant metastasis led us to examine the effect of PG545 on the progression of both primary tumor growth and the spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy setting. PG545 significantly inhibited primary tumor growth but importantly also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control and the sorafenib group, suggesting PG545's inhibitory effect on heparanase is indeed a critical attribute to induce anti-metastatic activity. In addition to blocking a common angiogenic signalling pathway in tumor cells, the expression of heparanase in the primary tumor and lung was also significantly reduced by PG545 treatment. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.

Multinational Companies, Technology Spillovers, and Plant Survival

OpenAIRE

Holger Görg; Eric Strobl

2003-01-01

This paper examines the effect of the presence of multinational companies on plant survival in the host country. We postulate that multinational companies can impact positively on plant survival through technology spillovers. We study the nature of the effect of multinationals using a Cox proportional hazard model which we estimate using plant level data for Irish manufacturing industries. Our results show that the presence of multinationals has a life enhancing effect only on indigenous plan...

Cultivation of sponge larvae: settlement, survival, and growth of juveniles

NARCIS (Netherlands)

Caralt, de S.; Otjens, H.; Uriz, M.J.; Wijffels, R.H.

2007-01-01

The aim of this study was to culture sponge juveniles from larvae. Starting from larvae we expected to enhance the survival and growth, and to decrease the variation in these parameters during the sponge cultures. First, settlement success, morphological changes during metamorphosis, and survival of

Mechano-Signal Transduction in Mesenchymal Stem Cells Induces Prosaposin Secretion to Drive the Proliferation of Breast Cancer Cells.

Science.gov (United States)

Ishihara, Seiichiro; Inman, David R; Li, Wan-Ju; Ponik, Suzanne M; Keely, Patricia J

2017-11-15

In response to chemical stimuli from cancer cells, mesenchymal stem cells (MSC) can differentiate into cancer-associated fibroblasts (CAF) and promote tumor progression. How mechanical stimuli such as stiffness of the extracellular matrix (ECM) contribute to MSC phenotype in cancer remains poorly understood. Here, we show that ECM stiffness leads to mechano-signal transduction in MSC, which promotes mammary tumor growth in part through secretion of the signaling protein prosaposin. On a stiff matrix, MSC cultured with conditioned media from mammary cancer cells expressed increased levels of α-smooth muscle actin, a marker of CAF, compared with MSC cultured on a soft matrix. By contrast, MSC cultured on a stiff matrix secreted prosaposin that promoted proliferation and survival of mammary carcinoma cells but inhibited metastasis. Our findings suggest that in addition to chemical stimuli, increased stiffness of the ECM in the tumor microenvironment induces differentiation of MSC to CAF, triggering enhanced proliferation and survival of mammary cancer cells. Cancer Res; 77(22); 6179-89. ©2017 AACR . ©2017 American Association for Cancer Research.

Pathophysiological hypoxia affects the redox state and IL-2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation.

Science.gov (United States)

Gaber, Timo; Tran, Cam Loan; Schellmann, Saskia; Hahne, Martin; Strehl, Cindy; Hoff, Paula; Radbruch, Andreas; Burmester, Gerd-Rüdiger; Buttgereit, Frank

2013-06-01

Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4(+) T cells. We found that pathophysiological hypoxia (<2% O2 ) significantly decreased CD4(+) T-cell survival after mitogenic stimulation. This effect was not due to an increased caspase-3/7-mediated apoptosis or adenosine-5'-triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O2 ) did not decrease CD4(+) T-cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T-cell proliferation and viability via disturbed IL-2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T-cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down-regulation of long-term T-cell activity in inflamed tissues. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

Science.gov (United States)

Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

2016-12-01

Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (PBMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both PBMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Survival Processing and the Stroop Task

Directory of Open Access Journals (Sweden)

Stephanie A. Kazanas

2015-11-01

Full Text Available This study was designed to investigate the impact of survival processing with a novel task for this paradigm: the Stroop color-naming task. As the literature is mixed with regard to task generalizability, with survival processing promoting better memory for words, but not better memory for faces or paired associates, these types of task investigations are important to a growing field of research. Using the Stroop task provides a unique contribution, as identifying items by color is an important evolutionary adaptation and not specific to humans as is the case with word recall. Our results indicate that survival processing, with its accompanying survival-relevance rating task, remains the best mnemonic strategy for word memory. However, our results also indicate that presenting the survival passage does not motivate better color-naming performance than color-naming alone. In addition, survival processing led to a larger amount of Stroop interference, though not significantly larger than the other conditions. Together, these findings suggest that considering one’s survival when performing memory and attention-based tasks does not enhance cognitive performance generally, although greater allocation of attentional resources to color-incongruent concrete objects could be considered adaptive. These findings support the notion that engaging in deeper processing via survival-relevance ratings may preserve these words across a variety of experimental manipulations.

Vitisin B, a resveratrol tetramer, inhibits migration through inhibition of PDGF signaling and enhancement of cell adhesiveness in cultured vascular smooth muscle cells

International Nuclear Information System (INIS)

Ong, Eng-Thaim; Hwang, Tsong-Long; Huang, Yu-Ling; Lin, Chwan-Fwu; Wu, Wen-Bin

2011-01-01

Vascular smooth muscle cells (VSMCs) play an important role in normal vessel formation and in the development and progression of cardiovascular diseases. Grape plants contain resveratrol monomer and oligomers and drinking of wine made from grape has been linked to 'French Paradox'. In this study we evaluated the effect of vitisin B, a resveratrol tetramer, on VSMC behaviors. Vitisin B inhibited basal and PDGF-induced VSMC migration. Strikingly, it did not inhibit VSMC proliferation but inversely enhanced cell cycle progression and proliferation. Among the tested resveratrol oligomers, vitisin B showed an excellent inhibitory activity and selectivity on PDGF signaling. The anti-migratory effect by vitisin B was due to direct inhibition on PDGF signaling but was independent of interference with PDGF binding to VSMCs. Moreover, the enhanced VSMC adhesiveness to matrix contributed to the anti-migratory effect by vitisin B. Fluorescence microscopy revealed an enhanced reorganization of actin cytoskeleton and redistribution of activated focal adhesion proteins from cytosol to the peripheral edge of the cell membrane. This was confirmed by the observation that enhanced adhesiveness was repressed by the Src inhibitor. Finally, among the effects elicited by vitisin B, only the inhibitory effect toward basal migration was partially through estrogen receptor activation. We have demonstrated here that a resveratrol tetramer exhibited dual but opposite actions on VSMCs, one is to inhibit VSMC migration and the other is to promote VSMC proliferation. The anti-migratory effect was through a potent inhibition on PDGF signaling and novel enhancement on cell adhesion. - Highlights: → Several resveratrol oligomers from grape plants are examined on VSMC behaviors. → Tetraoligomer vitisin B shows excellent inhibitory activity and selectivity. → It exerts dual but opposing actions: anti-migratory and pro-proliferative effects. → The anti-migratory effect results from anti

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

DEFF Research Database (Denmark)

Albers, Peter Hjorth; Bojsen-Moller, Kirstine N; Dirksen, Carsten

2015-01-01

Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose...... tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic-euglycemic clamp before as well as 1 week, 3 and 12 months after RYGB were analyzed for relevant insulin effector proteins/signaling components. Improvement in peripheral insulin sensitivity mainly occurred at 12 months post-surgery...... and glycogen synthase activity were enhanced 12 months post-surgery. In adipose tissue, protein expression of GLUT4, Akt2, TBC1D4 and acetyl-CoA carboxylase (ACC), phosphorylated levels of AMP-activated protein kinase and ACC as well as insulin-induced changes in phosphorylation of Akt and TBC1D4 were enhanced...

α-Lactose Improves the Survival of Septic Mice by Blockade of TIM-3 Signaling to Prevent NKT Cell Apoptosis and Attenuate Cytokine Storm.

Science.gov (United States)

Yao, Yao; Deng, Hai; Li, Pingfei; Zhang, Jian; Zhang, Junbo; Wang, Deping; Li, Songbo; Luo, Yixing; Wei, Zhengping; Bi, Guoyu; Yang, Xiang-Ping; Tang, Zhao-Hui

2017-03-01

Sepsis is the leading cause of death among critically ill patients and natural killer T (NKT) cell activation is essential to induce inflammatory cytokine cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed that T-cell immunoglobulin and mucin domain 3 (Tim-3) expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, interleukin (IL)-12 secreted by dendritic cell exposure to lipopolysaccharide increased the expression of Tim-3 in NKT cells. Administration of α-lactose to block Tim-3 signaling pathway significantly improved the survival of septic mice, concomitant with reduced IL-12 production by dendritic cells, reduced Tim-3 expression, prevented NKT cell apoptosis, and attenuated production of inflammatory cytokines. Collectively, Tim-3 signaling in NKT cells plays a critical role in the immunopathogenesis of sepsis. Thus, α-lactose could be a promising immunomodulatory agent in the treatment of sepsis.

Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

Directory of Open Access Journals (Sweden)

Fanren Tang

2017-09-01

Full Text Available Background/Aims: Neurite outgrowth and synaptogenesis are critical steps for functional recovery after stroke. Resveratrol promotes neurite outgrowth and synaptogenesis, but the underlying mechanism is not well understood, although the Sonic hedgehog (Shh signaling pathway may be involved. Given that resveratrol activates sirtuin (Sirt1, the present study examined whether this is mediated by Shh signaling. Methods: Primary cortical neuron cultures were pretreated with drugs before oxygen-glucose deprivation/reoxygenation (OGD/R. Cell viability and apoptosis were evaluated with Cell Counting Kit 8 and by terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Neurite outgrowth and synaptogenesis were assessed by immunocytochemistry and western blotting, which was also used to examine the expression of Sirt1 and Shh signaling proteins. Results: Resveratrol and the Smoothened (Smo agonist purmophamine, which activates Shh signaling, increased viability, reduced apoptosis, and stimulated neurite outgrowth after OGD/R injury. Moreover, the expression of growth-associated protein(GAP-43, synaptophysin, Shh, Patched (Ptc-1, Smo, glioma-associated oncogene homolog (Gli-1, and Sirt1 were upregulated under these conditions. These effects were reversed by treatment with the Smo inhibitor cyclopamine, whereas the Sirt1 inhibitor sirtinol reduced the levels of Shh, Ptc-1, Smo, and Gli-1. Conclusions: Resveratrol reduces neuronal injury following OGD/R injury and enhances neurite outgrowth and synaptogenesis by activating Shh signaling, which in turn induces Sirt1.

The enhanced greenhouse signal versus natural variations in observed climate time series: a statistical approach

Energy Technology Data Exchange (ETDEWEB)

Schoenwiese, C D [J.W. Goethe Univ., Frankfurt (Germany). Inst. for Meteorology and Geophysics

1996-12-31

It is a well-known fact that human activities lead to an atmospheric concentration increase of some IR-active trace gases (greenhouse gases GHG) and that this influence enhances the `greenhouse effect`. However, there are major quantitative and regional uncertainties in the related climate model projections and the observational data reflect the whole complex of both anthropogenic and natural forcing of the climate system. This contribution aims at the separation of the anthropogenic enhanced greenhouse signal in observed global surface air temperature data versus other forcing using statistical methods such as multiple (multiforced) regressions and neural networks. The competitive natural forcing considered are volcanic and solar activity, in addition the ENSO (El Nino/Southern Oscillation) mechanism. This analysis will be extended also to the NAO (North Atlantic Oscillation) and anthropogenic sulfate formation in the troposphere

The enhanced greenhouse signal versus natural variations in observed climate time series: a statistical approach

Energy Technology Data Exchange (ETDEWEB)

Schoenwiese, C.D. [J.W. Goethe Univ., Frankfurt (Germany). Inst. for Meteorology and Geophysics

1995-12-31

It is a well-known fact that human activities lead to an atmospheric concentration increase of some IR-active trace gases (greenhouse gases GHG) and that this influence enhances the `greenhouse effect`. However, there are major quantitative and regional uncertainties in the related climate model projections and the observational data reflect the whole complex of both anthropogenic and natural forcing of the climate system. This contribution aims at the separation of the anthropogenic enhanced greenhouse signal in observed global surface air temperature data versus other forcing using statistical methods such as multiple (multiforced) regressions and neural networks. The competitive natural forcing considered are volcanic and solar activity, in addition the ENSO (El Nino/Southern Oscillation) mechanism. This analysis will be extended also to the NAO (North Atlantic Oscillation) and anthropogenic sulfate formation in the troposphere

The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

Energy Technology Data Exchange (ETDEWEB)

Schaal, Courtney [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States); Padmanabhan, Jaya [Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave., Tampa, FL 33612 (United States); Chellappan, Srikumar, E-mail: Srikumar.Chellappan@moffitt.org [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States)

2015-07-31

Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

International Nuclear Information System (INIS)

Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

2015-01-01

Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer

Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.

Directory of Open Access Journals (Sweden)

Daniel Thomas

Full Text Available The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K, promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting

Aberrant Signaling Pathways in Glioma

International Nuclear Information System (INIS)

Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

2011-01-01

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

Relationship between Length and Surface-Enhanced Raman Spectroscopy Signal Strength in Metal Nanoparticle Chains: Ideal Models versus Nanofabrication

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Kristen D. Alexander

2012-01-01

Full Text Available We have employed capillary force deposition on ion beam patterned substrates to fabricate chains of 60 nm gold nanospheres ranging in length from 1 to 9 nanoparticles. Measurements of the surface-averaged SERS enhancement factor strength for these chains were then compared to the numerical predictions. The SERS enhancement conformed to theoretical predictions in the case of only a few chains, with the vast majority of chains tested not matching such behavior. Although all of the nanoparticle chains appear identical under electron microscope observation, the extreme sensitivity of the SERS enhancement to nanoscale morphology renders current nanofabrication methods insufficient for consistent production of coupled nanoparticle chains. Notwithstanding this fact, the aggregate data also confirmed that nanoparticle dimers offer a large improvement over the monomer enhancement while conclusively showing that, within the limitations imposed by current state-of-the-art nanofabrication techniques, chains comprising more than two nanoparticles provide only a marginal signal boost over the already considerable dimer enhancement.

Speech enhancement

CERN Document Server

Benesty, Jacob; Chen, Jingdong

2006-01-01

We live in a noisy world! In all applications (telecommunications, hands-free communications, recording, human-machine interfaces, etc.) that require at least one microphone, the signal of interest is usually contaminated by noise and reverberation. As a result, the microphone signal has to be ""cleaned"" with digital signal processing tools before it is played out, transmitted, or stored.This book is about speech enhancement. Different well-known and state-of-the-art methods for noise reduction, with one or multiple microphones, are discussed. By speech enhancement, we mean not only noise red

Neurotrophin Signaling via TrkB and TrkC Receptors Promotes the Growth of Brain Tumor-initiating Cells*

Science.gov (United States)

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A.; Fournier, Michelle; Vrionis, Frank D.; Tran, Nam; Chan, Jennifer A.; Kenchappa, Rajappa S.; Forsyth, Peter A.

2015-01-01

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. PMID:25538243

Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.

Science.gov (United States)

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A; Fournier, Michelle; Vrionis, Frank D; Tran, Nam; Chan, Jennifer A; Kenchappa, Rajappa S; Forsyth, Peter A

2015-02-06

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Acute High-intensity Interval Exercise-induced Redox Signaling is Associated with Enhanced Insulin Sensitivity in Obese Middle-aged Men.

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Lewan Parker

2016-09-01

Full Text Available Background. Obesity and ageing are associated with increased oxidative stress, activation of stress and mitogen activated protein kinases (SAPK, and the development of insulin resistance and metabolic disease. In contrast, acute exercise also increases oxidative stress and SAPK signaling, yet is reported to enhance insulin sensitivity and reduce the risk of metabolic disease. This study explored this paradox by investigating the effect of a single session of high-intensity interval-exercise (HIIE on redox status, muscle SAPK and insulin protein signaling in eleven middle-aged obese men. Methods. Participants completed a 2 hour hyperinsulinaemic-euglycaemic clamp at rest, and 60 minutes after HIIE (4x4 mins at 95% HRpeak; 2 min recovery periods, separated by 1-3 weeks. Results. Irrespective of exercise-induced changes to redox status, insulin stimulation both at rest and after HIIE similarly increased plasma superoxide dismutase activity, plasma catalase activity, and skeletal muscle 4-HNE; and significantly decreased plasma TBARS and hydrogen peroxide. The SAPK signaling pathways of p38 MAPK, NF-κB p65, and JNK, and the distal insulin signaling protein AS160Ser588, were activated with insulin stimulation at rest and to a greater extent with insulin stimulation after a prior bout of HIIE. Higher insulin sensitivity after HIIE was associated with higher insulin-stimulated SAPK phosphorylation (JNK, p38 MAPK and NF-κB and SOD activity (p<0.05. Conclusion. These findings support a role for redox homeostasis and SAPK signaling in insulin-stimulated glucose uptake which may contribute to the enhancement of insulin sensitivity in obese men 3 hours after HIIE.

A dual-color fluorescence-based platform to identify selective inhibitors of Akt signaling.

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Aranzazú Rosado

Full Text Available BACKGROUND: Inhibition of Akt signaling is considered one of the most promising therapeutic strategies for many cancers. However, rational target-orientated approaches to cell based drug screens for anti-cancer agents have historically been compromised by the notorious absence of suitable control cells. METHODOLOGY/PRINCIPAL FINDINGS: In order to address this fundamental problem, we have developed BaFiso, a live-cell screening platform to identify specific inhibitors of this pathway. BaFiso relies on the co-culture of isogenic cell lines that have been engineered to sustain interleukin-3 independent survival of the parental Ba/F3 cells, and that are individually tagged with different fluorescent proteins. Whilst in the first of these two lines cell survival in the absence of IL-3 is dependent on the expression of activated Akt, the cells expressing constitutively-activated Stat5 signaling display IL-3 independent growth and survival in an Akt-independent manner. Small molecules can then be screened in these lines to identify inhibitors that rescue IL-3 dependence. CONCLUSIONS/SIGNIFICANCE: BaFiso measures differential cell survival using multiparametric live cell imaging and permits selective inhibitors of Akt signaling to be identified. BaFiso is a platform technology suitable for the identification of small molecule inhibitors of IL-3 mediated survival signaling.

Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

Energy Technology Data Exchange (ETDEWEB)

Tang, T.Y.; Sadat, U. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom); Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Miller, S.R. [GlaxoSmithKline, Biostatistics and Data Sciences, Harlow (United Kingdom); Walsh, S.R.; Boyle, J.R.; Gaunt, M.E. [Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom)

2009-07-15

Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T{sub 1}-weighted (T{sub 1}w), T{sub 2}*-weighted (T{sub 2}*w) and quantitative T{sub 2}* (qT{sub 2}*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T{sub 1}w, T{sub 2}*w and qT{sub 2}* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T{sub 1}w, T{sub 2}*w and qT{sub 2}* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T{sub 1}w, T{sub 2}*w and qT{sub 2}*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T{sub 1}w, T{sub 2}*w and qT{sub 2}* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

International Nuclear Information System (INIS)

Tang, T.Y.; Sadat, U.; Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H.; Miller, S.R.; Walsh, S.R.; Boyle, J.R.; Gaunt, M.E.

2009-01-01

Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T 1 -weighted (T 1 w), T 2 *-weighted (T 2 *w) and quantitative T 2 * (qT 2 *) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T 1 w, T 2 *w and qT 2 * MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T 1 w, T 2 *w and qT 2 * sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T 1 w, T 2 *w and qT 2 *, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T 1 w, T 2 *w and qT 2 * signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

Glycyrrhetic acid synergistically enhances β₂-adrenergic receptor-Gs signaling by changing the location of Gαs in lipid rafts.

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Qian Shi

Full Text Available Glycyrrhetic acid (GA exerts synergistic anti-asthmatic effects via a β₂-adrenergic receptor (β₂AR-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β₂AR-Gs-adenylate cyclase (AC-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β₂AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA was synthesized and applied to human embryonic kidney 293 (HEK293 cells expressing fusion β₂AR, and the electron spin resonance (ESR technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β₂AR and Gαs, as well as in reduced β₂AR internalization. Co-localization of β₂AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β₂AR-protein kinase A (PKA signaling pathway was proposed. The enhanced efficacy of β₂AR agonists by this novel mechanism could prevent tachyphylaxis.

MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN

International Nuclear Information System (INIS)

Tan, Guangyun; Shi, Yuling; Wu, Zhao-Hui

2012-01-01

Highlights: ► miR-22 is induced in cells treated with UV radiation. ► ATM is required for miR-22 induction in response to UV. ► miR-22 targets 3′-UTR of PTEN to repress its expression in UV-treated cells. ► Upregulated miR-22 inhibits apoptosis in cells exposed to UV. -- Abstract: DNA damage response upon UV radiation involves a complex network of cellular events required for maintaining the homeostasis and restoring genomic stability of the cells. As a new class of players involved in DNA damage response, the regulation and function of microRNAs in response to UV remain poorly understood. Here we show that UV radiation induces a significant increase of miR-22 expression, which appears to be dependent on the activation of DNA damage responding kinase ATM (ataxia telangiectasia mutated). Increased miR-22 expression may result from enhanced miR-22 maturation in cells exposed to UV. We further found that tumor suppressor gene phosphatase and tensin homolog (PTEN) expression was inversely correlated with miR-22 induction and UV-induced PTEN repression was attenuated by overexpression of a miR-22 inhibitor. Moreover, increased miR-22 expression significantly inhibited the activation of caspase signaling cascade, leading to enhanced cell survival upon UV radiation. Collectively, these results indicate that miR-22 is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTEN expression.

Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive G{sub s}–G protein signaling in osteoblasts

Energy Technology Data Exchange (ETDEWEB)

Wattanachanya, Lalita, E-mail: lalita_md@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok (Thailand); Wang, Liping, E-mail: lipingwang05@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Millard, Susan M., E-mail: susan.millard@mater.uq.edu.au [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Lu, Wei-Dar, E-mail: weidar_lu@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); O’Carroll, Dylan, E-mail: dylancocarroll@gmail.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Hsiao, Edward C., E-mail: Edward.Hsiao@ucsf.edu [Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA (United States); Conklin, Bruce R., E-mail: bconklin@gladstone.ucsf.edu [Gladstone Institute of Cardiovascular Disease, San Francisco, CA (United States); Department of Medicine, University of California, San Francisco, CA (United States); Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA (United States); Nissenson, Robert A., E-mail: Robert.Nissenson@ucsf.edu [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States)

2015-05-01

G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active G{sub s}-coupled GPCR, under the control of the 2.3 kb Col I promoter. These mice showed a dramatic age-dependent increase in trabecular bone of femurs. Here, we further evaluated the effects of enhanced G{sub s} signaling in OBs on intramembranous bone formation by examining calvariae of 1- and 9-week-old Col1(2.3)/Rs1 mice and characterized the in vivo gene expression specifically occurring in osteoblasts with activated G{sub s} G protein-coupled receptor signaling, at the cellular level rather than in a whole bone. Rs1 calvariae displayed a dramatic increase in bone volume with partial loss of cortical structure. By immunohistochemistry, Osterix was detected in cells throughout the inter-trabecular space while Osteocalcin was expressed predominantly in cells along bone surfaces, suggesting the role of paracrine mediators secreted from OBs driven by 2.3 kb Col I promoter could influence early OB commitment, differentiation, and/or proliferation. Gene expression analysis of calvarial OBs revealed that genes affected by Rs1 signaling include those encoding proteins important for cell differentiation, cytokines and growth factors, angiogenesis, coagulation, and energy metabolism. The set of G{sub s}-GPCRs and other GPCRs that may contribute to the observed skeletal phenotype and candidate paracrine mediators of the effect of G{sub s} signaling in OBs were also determined. Our results identify novel detailed in vivo cellular changes of the anabolic response of the skeleton to G{sub s} signaling in mature OBs. - Highlights: • OB expression of an engineered G{sub s}-coupled receptor dramatically increases bone mass. • We investigated the changes in gene expression in vivo in enhanced OB G{sub s} signaling. • Genes in cell cycle and transcription were increased in

Exponential signaling gain at the receptor level enhances signal-to-noise ratio in bacterial chemotaxis.

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Silke Neumann

Full Text Available Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly designed signaling architectures. Here, we report on a novel control mechanism that allows living cells to keep precision in their signaling characteristics - stationary pathway output, response amplitude, and relaxation time - in the presence of strong intracellular perturbations. The concept relies on the surprising fact that for systems showing perfect adaptation an exponential signal amplification at the receptor level suffices to eliminate slowly varying multiplicative noise. To show this mechanism at work in living systems, we quantified the response dynamics of the E. coli chemotaxis network after genetically perturbing the information flux between upstream and downstream signaling components. We give strong evidence that this signaling system results in dynamic invariance of the activated response regulator against multiplicative intracellular noise. We further demonstrate that for environmental conditions, for which precision in chemosensing is crucial, the invariant response behavior results in highest chemotactic efficiency. Our results resolve several puzzling features of the chemotaxis pathway that are widely conserved across prokaryotes but so far could not be attributed any functional role.

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

International Nuclear Information System (INIS)

Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

2012-01-01

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

C. elegans AMPKs promote survival and arrest germline development during nutrient stress

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Masamitsu Fukuyama

2012-08-01

Mechanisms controlling development, growth, and metabolism are coordinated in response to changes in environmental conditions, enhancing the likelihood of survival to reproductive maturity. Much remains to be learned about the molecular basis underlying environmental influences on these processes. C. elegans larvae enter a developmentally dormant state called L1 diapause when hatched into nutrient-poor conditions. The nematode pten homologue daf-18 is essential for maintenance of survival and germline stem cell quiescence during this period (Fukuyama et al., 2006; Sigmond et al., 2008, but the details of the signaling network(s in which it functions remain to be elucidated. Here, we report that animals lacking both aak-1 and aak-2, which encode the two catalytic α subunits of AMP-activated protein kinase (AMPK, show reduced viability and failure to maintain mitotic quiescence in germline stem cells during L1 diapause. Furthermore, failure to arrest germline proliferation has a long term consequence; aak double mutants that have experienced L1 diapause develop into sterile adults when returned to food, whereas their continuously fed siblings are fertile. Both aak and daf-18 appear to maintain germline quiescence by inhibiting activity of the common downstream target, TORC1 (TOR Complex 1. In contrast, rescue of the lethality phenotype indicates that aak-2 acts not only in the intestine, as does daf-18, but also in neurons, likely promoting survival by preventing energy deprivation during L1 diapause. These results not only provide evidence that AMPK contributes to survival during L1 diapause in a manner distinct from that by which it controls dauer diapause, but they also suggest that AMPK suppresses TORC1 activity to maintain stem cell quiescence.

Methamphetamine-enhanced female sexual motivation is dependent on dopamine and progesterone signaling in the medial amygdala.

Science.gov (United States)

Holder, Mary K; Veichweg, Shaun S; Mong, Jessica A

2015-01-01

Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and impulsive sexual behaviors that often lead to unsafe sexual practices. In women METH users, such practices have been associated with increases in unplanned pregnancies and sexually transmitted diseases. Despite this significant heath concern, the neural mechanisms underlying this drug-sex association are not known. We previously established a rodent model of METH-facilitated female sexual behavior in which estradiol and progesterone interact with METH to increase motivational components of female behavior and neuronal activation in the posterodorsal medial amygdala (MePD) (Holder et al., 2010; Holder and Mong, 2010). The current study more directly examines the mechanisms underlying the drug-sex interaction. Here, we hypothesize that METH-induced increases in MePD dopamine signaling bridge the METH-hormone interaction. In support of this hypothesis, we found that excitotoxic lesions targeted to the MePD attenuated the METH-induced increases in proceptive behavior. Furthermore, infusion of a D1 agonist into the MePD increased proceptive behavior, while infusion of a D1 antagonist blocked the ability of METH to increase proceptive behaviors. Additionally, we found that METH-treatment increased progesterone receptor (PR) immunoreactivity in the MePD, suggesting an interaction between dopamine and progesterone signaling. Indeed, infusions of the PR antagonist, RU486, prevented METH-induced increases in sexual behavior. Thus, taken together, the current findings suggest that dopamine in the MePD modulates enhanced sexual motivation via an amplification of progesterone signaling and contributes to a better understanding of the neurobiology of drug-enhanced sexual behaviors. Copyright © 2014 Elsevier Inc. All rights reserved.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

KAUST Repository

Liao, Hsin-Wei; Hsu, Jung-Mao; Xia, Weiya; Wang, Hung-Ling; Wang, Ying-Nai; Chang, Wei-Chao; Arold, Stefan T.; Chou, Chao-Kai; Tsou, Pei-Hsiang; Yamaguchi, Hirohito; Fang, Yueh-Fu; Lee, Hong-Jen; Lee, Heng-Huan; Tai, Shyh-Kuan; Yang, Mhu-Hwa; Morelli, Maria P.; Sen, Malabika; Ladbury, John E.; Chen, Chung-Hsuan; Grandis, Jennifer R.; Kopetz, Scott; Hung, Mien-Chie

2015-01-01

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

KAUST Repository

Liao, Hsin-Wei

2015-11-16

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

Science.gov (United States)

Liao, Hsin-Wei; Hsu, Jung-Mao; Xia, Weiya; Wang, Hung-Ling; Wang, Ying-Nai; Chang, Wei-Chao; Arold, Stefan T.; Chou, Chao-Kai; Tsou, Pei-Hsiang; Yamaguchi, Hirohito; Fang, Yueh-Fu; Lee, Hong-Jen; Lee, Heng-Huan; Tai, Shyh-Kuan; Yang, Mhu-Hwa; Morelli, Maria P.; Sen, Malabika; Ladbury, John E.; Chen, Chung-Hsuan; Grandis, Jennifer R.; Kopetz, Scott; Hung, Mien-Chie

2015-01-01

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment. PMID:26571401

Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

Science.gov (United States)

2015-01-01

Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients. PMID:26560447

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

Science.gov (United States)

Jamieson, Cara; Lui, Christina; Brocardo, Mariana G.; Martino-Echarri, Estefania; Henderson, Beric R.

2015-01-01

ABSTRACT β-Catenin transduces the Wnt signaling pathway and its nuclear accumulation leads to gene transactivation and cancer. Rac1 GTPase is known to stimulate β-catenin-dependent transcription of Wnt target genes and we confirmed this activity. Here we tested the recent hypothesis that Rac1 augments Wnt signaling by enhancing β-catenin nuclear import; however, we found that silencing/inhibition or up-regulation of Rac1 had no influence on nuclear accumulation of β-catenin. To better define the role of Rac1, we employed proximity ligation assays (PLA) and discovered that a significant pool of Rac1–β-catenin protein complexes redistribute from the plasma membrane to the nucleus upon Wnt or Rac1 activation. More importantly, active Rac1 was shown to stimulate the formation of nuclear β-catenin–lymphoid enhancer factor 1 (LEF-1) complexes. This regulation required Rac1-dependent phosphorylation of β-catenin at specific serines, which when mutated (S191A and S605A) reduced β-catenin binding to LEF-1 by up to 50%, as revealed by PLA and immunoprecipitation experiments. We propose that Rac1-mediated phosphorylation of β-catenin stimulates Wnt-dependent gene transactivation by enhancing β-catenin–LEF-1 complex assembly, providing new insight into the mechanism of cross-talk between Rac1 and canonical Wnt/β-catenin signaling. PMID:26403202

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