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Melchjorsen, Jesper PhD*; Risør, Michael W MSc*; Søgaard, Ole S MD*; O'Loughlin, Kieran L MSc†; Chow, Sue BSc‡; Paludan, Søren R PhD§; Ellermann-Eriksen, Svend MD, PhD‖; Hedley, David W MD, PhD‡; Minderman, Hans PhD†; Østergaard, Lars MD, PhD*; Tolstrup, Martin PhD*
From the *Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark; †Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY; ‡Ontario Cancer Institute, Princess Margarets Hospital, Toronto, Canada; §Department of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark; ‖Department of Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark.
Received for publication January 17, 2011; accepted March 2, 2011.
Supported by grants from the Danish AIDS Foundation, the Scandinavian Society of Antimicrobial Chemotherapy (SSAC), the Aase and Ejnar Danielsen Foundation, Region Midts Forskningsfond, the Augustinus Foundation, the Dagmar Marshall Foundation, Fonden til Lægevidenskabens Fremme, and the King Christian X Foundation.
Part of the article's data was presented in a poster at the 27th Annual Meeting of the Scandinavian Society of Antimicrobial Chemotherapy (SSAC); September 30, 2010, to November 3, 2010; Stockholm, Sweden.
The authors declare that they do not have any competing financial interests.
M. W. Risør is recipient of a scholarship from the Danish Cancer Foundation. O. S. Søgaard is recipient of a fellowship from University of Aarhus.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).
Correspondence to: Jesper Melchjorsen, PhD, Department of Infectious Diseases, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. (e-mail: email@example.com).
Objectives: In this study, we aimed to investigate the possible immune modulatory effects of HIV nucleoside reverse transcriptase inhibitors during secondary infections and inflammation, focusing on inflammatory cytokine responses and the interleukin (IL)-12/IL-10 balance.
Methods: We investigated the in vitro effect of tenofovir and zidovudine (AZT) on production of proinflammatory cytokines in monocytes and human peripheral blood mononuclear cells (PBMCs). Stimulation panels included Toll-Like receptor (TLR) ligands; the inflammation mediator tumor necrosis factor-α; and the pathogens cytomegalovirus, Neisseria meningitides, Escherichia coli, and Streptococcus pneumoniae. Cytokine levels were measured using enzyme-linked immunosorbent assay and luminex technology. RNA levels were assessed using real-time polymerase chain reaction. Activity of mitogen-activated protein kinase and NF-κB signaling was evaluated using flow cytometry and multispectral imaging cytometry, respectively.
Results: Tenofovir decreased and AZT increased both IL-8 and CCL3 production from monocytes after stimulation with TLR ligands, tumor necrosis factor-α, or live pathogens. Similarly, tenofovir decreased CCL3 levels in human PBMCs. Furthermore, tenofovir strongly decreased induction of IL-10 but increased levels of IL-12. AZT did not affect IL-12 or IL-10 levels. The observed drug-induced changes in cytokine production were independent from transcriptional regulation through the mitogen-activated protein kinase and nuclear factor kappa B pathways.
Conclusions: Our data suggest divergent effects of tenofovir and AZT on proinflammatory responses in monocytes (CCL3 and IL-8) and PBMCs (CCL3). Moreover, tenofovir shifts the IL-10/IL-12 balance after cell stimulation with TLR ligands or infection with live bacteria, thus suggesting that the choice of nucleoside reverse transcriptase inhibitor affects overall inflammation and early immune responses against secondary pathogens.
The introduction of highly active antiretroviral therapy has substantially decreased the risk of infections in persons with HIV through repression of viral replication and normalization of the CD4+ count.1,2 Nevertheless, patients with HIV on treatment still show increased susceptibility to secondary infections, such as pneumonia and bacterial meningitis, compared with persons without HIV.2,3 Possible mechanisms could be loss of immunological and epithelial integrity, fibrosis of lymphatic tissue, and loss of interleukin (IL)-17 expressing CD4+ T lymphocytes from the gastrointestinal tract, leading to microbial translocation and generalized immune activation.4,5 Furthermore, the imbalance in immune function could be related to immune modulatory properties of the antiretroviral drugs, as particular treatments regimes have been shown to affect cytokine networks regulating immunity.6-10 Nucleoside reverse transcriptase inhibitors (NRTIs) have not been investigated with regard to immune responses to secondary infections.
Microbial invasions, including infections in patients with HIV-1, are sensed by germ line-encoded pathogen recognition receptors, including Toll-Like receptors (TLRs). TLR triggering induces the production of proinflammatory cytokines. Regulated cytokine responses are important for immune responses, and a dysregulated cytokine response may be detrimental for the host.11
Acyclic nucleoside phosphonates, including tenofovir, have been shown to induce cytokine mRNA in murine macrophages,12 accumulation of cytokines [IL-1β, tumor necrosis factor (TNF-α), CCL3, and IL-10] in murine peritoneal cell culture,13 and CCL3 ad CCL5 in human peripheral blood mononuclear cells (PBMCs).7 Abacavir induces early changes in cells, including redistribution of heat-shock protein 70.14 Zidovudine (AZT) reportedly affects intracellular signaling differently in different cell types. For instance, AZT has been shown to activate nuclear factor kappa B (NF-κB) in monocyte-like U937 cells, the promyelocytic leukemia cell line HL60, and the T-lymphoblastic cell line MOLT.15 In contrast, AZT has been reported to inhibit NF-κB activation in Burkitt lymphoma B cells.16
IL-8 and CCL3 (macrophage inflammatory protein 1α [MIP-1α]) are inflammatory mediators broadly induced by infection with pathogens and via inflammatory signals. IL-8 is an important neutrophil and CD4+ T-cell chemoattractant and thus plays a pivotal role in the early innate response against invading pathogens as a regulator of adaptive responses.17,18 IL-8 affects HIV-1 pathogenesis in many ways. IL-8 stimulates HIV replication in both monocyte-derived macrophages and T cells, increases transmission of HIV-1 in cervical transplants, and is associated with inflammation.17-20 Furthermore, IL-8 enhances replication of cytomegalovirus (CMV) in human fibroblasts21 and reduces antiviral effects of IFN-α.22 CCL3 is an inflammatory chemokine produced by a variety of cells. CCL3 inhibits infection with M-tropic HIV, via binding to the chemokine receptor CCR5,23 and is an important factor for host defense against HIV, evidenced by the finding that genetic deficiency in CCL3 is associated with increased risk of perinatal HIV-1 transmission in humans and faster progression to simian AIDS in macaques.24-27 However, CCL3 may also play a negative role in HIV pathogenesis because CCL3 is associated with inflammation-mediated diseases and tissue injury, including gastrointestinal and respiratory diseases.28
The IL-10 and IL-12 balance is dysregulated in patients with HIV. IL-12 plays a pivotal role in regulating cell-mediated immunity essential for control of HIV and secondary infections.29,30 Although IL-12 levels are elevated during acute HIV infection,31 an impaired IL-12 response is observed later in infection. The hampered IL-12 response is associated with increased HIV disease severity and faster progression to AIDS.32-34 At the cellular level, PBMCs from patients with HIV are impaired in their IL-12 production in response to bacterial and mitogen stimuli.35 IL-10 is a key molecule in immune suppression, terminating inflammatory responses and inhibiting activation and effector functions of T cells, macrophages, and monocytes.36,37 IL-10 is a main inhibitor of IL-12 production,38 and the presence of IL-10 can result in anergy and nonresponsiveness to infections and antigens, including HIV-derived antigens.36,37 HIV-1 induces IL-10 in monocytes, CD4+ and CD8+ T cells,39-42 and IL-10 induces expression of the HIV-1 coreceptor CCR5 in human monocytes and neutrophils.43 Further suggesting an important role for IL-10 during HIV progression, a higher frequency of IL-10-producing CD4+ T cells, is seen in HIV-1-infected individuals with progressive HIV-1 compared with cells from nonprogressors.40
In this work, we investigated the effect of tenofovir and AZT both on the proinflammatory responses focusing on the cytokines IL-8 and CCL3, due to their induction by several pathways, thus allowing delineation of specific effects of tenofovir and ziduvudine on pathogen-activated, single TLR-activated pathways and after inflammatory signal by TNF-α. Furthermore, we investigated the IL-10/IL-12 balance in human primary cells after challenge with live pathogens, TLR stimulation, and stimulation with the inflammatory mediator TNF-α.
Pure compound AZT, the prodrug tenofovir disoproxil fumarate (tenofovir DF), tenofovir, and abacavir were obtained from the AIDS Research and Reference Reagent Program, National Institute of Allergy and Infectious Diseases, and National Institutes of Health. Five millimolar stocks of synthetic NRTIs tenofovir DF, tenofovir, and AZT were made in sterile water. Abacavir was solubilized in dimethyl sulfoxid (DMSO), and subsequently, all stocks were stored at −20°C. Tablets containing tenofovir DF (Viread; Gilead, Foster City, California) abacavir (Ziagen; GlaxoSmithKline Brentford, United Kingdom) and AZT (Retrovir; GlaxoSmithKline) were solubilized in DMSO for stock concentration 20 mM. Stock solutions were sterile filtered and stored at −20°C.
Monocytic U937 cells, THP-1 cells, and PBMCs were cultured in RPMI 1640 supplemented with l-glutamin (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES]), penicillin, and streptomycin and 10% heat-inactivated fetal bovine serum (Invitrogen). PBMCs were isolated from blood obtained from healthy donors by Isopaque-Ficoll separation. MRC-5 fibroblasts were grown in Dulbecco Modified Eagle Medium (DMEM) containing 10% fetal bovine serum and penicillin/streptomycin (Invitrogen). PBMCs were seeded in 96-well culture plates at a density of 2 × 105 cells per well or 1 × 106 cells per 6-well plate and cultured overnight before further treatment. U937 cells and THP-1 cells were seeded at a density of 2 × 105 cells per 96-well plate or 1 × 106 cells per 6-well plate 3 hours before further treatment. For ImageStream experiments, U937 cells were used at a concentration of 3 × 106 cells per milliliter.
Clinical bacterial isolates of Escherichia coli, Neisseria meningitides, and Streptococcus pneumoniae were grown overnight in brain heart infusion broth with 10% Levinthal broth. CMV strain AD169 was grown in fibroblasts MRC-5 cells until full cytopathic effect was seen (7-9 days). Cell culture media containing virus and control media from mock-infected cells were cleared from cell debris by centrifugation and stored at −80°C until experiments. The virus titer was approximately 4 × 106 plaque-forming units per milliliter determined by titration on MRC-5 cells. Briefly, confluent MRC-5 cells were infected with 10-fold dilutions of CMV. After 3 days of infection, cells were washed with PBS and fixed with 80% acetone for 10 minutes. After rinsing, the cells were incubated with 1:10 diluted monoclonal anti-CMV antibody (Dako, Glostrup, Denmark) for 30 minutes and subsequently incubated 30 minutes with fluorescein isothiocyanate-conjugated goat anti-murine F(ab)2 antibody (Dako). CMV-positive cells were visualized by fluorescence microscopy.
NRTIs were diluted in growth media before use. Similar volume of vehicle (DMSO or water) was used as control. Cells were pretreated with indicated concentrations of drug for the indicated time before stimulation with TLR2 ligands Pam3CSK4 (200 ng/mL; InvivoGen, Toulouse, France), TLR4 ligand lipopolysaccharide (LPS) (100 ng/mL; Sigma -Aldrich, Copenhagen, Denmark), TLR7/8 ligand CL097 (1 μg/mL; InvivoGen), or TNF-α (25 ng/mL; R&D Systems, Abingdon, United Kingdom). Freshly grown E. coli was added to cell culture in multiplicity of infection (MOI) of 10. Neisseria meningitidis and S. pneumoniae were added to the cell culture in MOI of 4. CMV was used in MOI of 0.5. As control for bacterial and CMV infection, uninfected broth or mock cell culture media was used, respectively. At indicated time, cell culture was harvested for detection of cytokine levels or total RNA was harvested for reverse transcriptase—polymerase chain reaction analysis.
Harvested cell culture supernatants were assayed using Duoset enzyme-linked immunosorbent assays (ELISAs) for IL-8, CCL3 (MIP-1α), and IL-6 (R&D Systems) or Cytoset ELISAs for IL-1β, IFN-γ, IL-10, or IL-12p40/p70 (Invitrogen). For some experiments, IL-8 levels were determined by multiplex bead array (Luminex) using IL-8-specific kits (Invitrogen). ELISAs and bead arrays were performed as specified by the manufacturers.
Total RNA was extracted using Trizol as described by the manufacturer (Invitrogen) and stored at −80°C. cDNA synthesis was done using the moloney murine leukemia virus reverse transcriptase (MMLV-RT), according to the manufacturer's instructions (Invitrogen). Gene expression was determined using SYBR Green qPCR mix (Qiagen Copenhagen, Denmark). Gene-specific primers were designed using Primerblast (http://www.ncbi.nlm.nih.gov/tools/primer-blast/). To avoid amplification of chromosomal DNA, primers were designed to span an exon-exon junction or be separated by one intron. RNA not subjected to reverse transcription was used as a negative control for polymerase chain reaction (PCR) amplification. The gene-specific primers were as follows: GAPDH forward, 5'-CGACCACTTTGTCAAGCTCA-3'; GAPDH reverse, 5'-GGTGGTCCAGGGGTCTTACT-3'; IL-8 forward, 5'-CTGCGCCAACACAGAAATTA-3'; IL-8 reverse, 5'-TGAATTCTCAGCCCTCTTCAA-3'; IL-12p40 forward, 5'-GCAGCTTCTTCATCAGGGAC-3'; IL-12p40 reverse, 5'-AGGGTACTCCCAGCTGACCT-3'; IL-10 forward, 5'-CCAGACCCAGACATCAAGGC-3'; IL-10 reverse, 5'-GGCCTTGCTCTTGTTTTCAC-3'. qPCR was performed on a LightCycler 2.0 instrument (Roche, Hvidovre, Denmark), and crossing point values were determined using the LightCycler software v. 4.05 (Roche). Relative gene expression levels were calculated as previously described using GAPDH as the housekeeping reference gene.44
Freshly drawn whole blood was pretreated with tenofovir DF (250 μM), the mitogen-activated protein kinase (MAPK) inhibitor U0126 (100 μM; Promega, Madison, Wisconsin), or vehicle as control (15 minutes at 37°C). Subsequently, the cells were incubated with LPS (1 μg/mL) for 30 minutes at 37°C and cells were stained, as previously described,45 using anti-CD45-KO, anti-CD14-PC7, anti-phospho-extracellular signal-regulated kinase (ERK)Alexa647, and anti-phospho-p38MAPK-Alexa488 (all from Beckman Coulter, Birkeroed, Denmark). Flow analysis was performed on a Gallios flow cytometer (Beckman Coulter) and data analysis using Kaluza software (Beckman Coulter).
U937 or PBMCs were incubated with tenofovir DF (250 μM) or saquinavir (100 μM) for 15 minutes before subsequent stimulation with TNF-α (100 ng/mL) or LPS (1000 ng/mL) for 30 minutes. Cells were harvested and then fixed using 4% formaldehyde (Polysciences, Warrington, Pennsylvania) for 10 minutes after which the cells were permeabilized using 0.1% triton X-100 and stained with 1:20-diluted rabbit anti-p65 antibody (Santa Cruz) at room temperature for 30 minutes, followed by incubation for 30 minutes at room temperature with fluorescein isothiocyanate-conjugated F(ab)2 donkey anti-rabbit IgG antibody (Jackson Immunoresearch, West Grove, Pennsylvania). Before analysis, nuclei were stained using 4',6-diamidino-2-phenylindole (DAPI). Samples were analyzed on an ImageStreamX imaging Cytometer (Amnis, Seattle, Washington), which simultaneously acquires spectrally separated spatially correlated images from each individual cell. The nuclear translocation of NF-κB (p65), quantitatively determined as the so-called similarity score between the nuclear (DAPI) and NF-κB (p65) images of each cell, was used as a parameter of NF-κB signaling activity as described previously.46
To evaluate how HIV NRTIs affect immune cells, we pretreated monocytic U937 cells with NRTIs tenofovir DF (Viread), AZT (Retrovir), or abacavir (Ziagen) for 1 hour and subsequently stimulated the cells with the TLR2 or TLR4 agonists (Pam3CSK4 and LPS, respectively). The concentrations used did not affect cell viability within the duration of the studies (not shown), and concentrations were in line with concentrations used by others for in vitro studies.7,12,13,16,47 After 20 hours, cell supernatants were harvested and assayed for IL-8 using Luminex. AZT or abacavir did not significantly affect TLR2-induced IL-8, whereas tenofovir reduced levels of IL-8 (Fig. 1A). Tenofovir in its processed form, however, did not induce IL-8 and compared with the prodrug tenofovir DF only very modestly affected levels of TLR-induced IL-8 (Fig. 1B). To evaluate whether the effect seen was directly linked to the active components of the drugs, similar experiments were done using pure components. AZT in pure form induced IL-8 and CCL3 and increased TLR- and TNF-α-induced IL-8 and CCL3 secretion (Figs. 1C, E). IL-1β and IL-6 were investigated, but because both were not induced in U937 cells (not shown), only CCL3 and IL-8 were assessed further. In accordance with results gained using solubilized tablets (Fig. 1A), pure synthetic prodrug tenofovir DF decreased IL-8 and CCL3 levels induced by TLR agonists and by TNF-α stimulation (Figs. 1B, C, E). Abacavir did not affect TLR4-, TLR7/8-, or TNF-α-activated IL-8 or CCL3 or stimulation (Figs. 1D, F). Thus, tenofovir DF and AZT differentially affect TLR- and TNF-α-induced cytokine production in monocyte U937 cells, whereas abacavir does not affect proinflammatory cytokine production.
To evaluate dose-dependency, we pretreated U937 cells with increasing concentrations of tenofovir DF or AZT before stimulation with ligands for TLR2, TLR4, and TLR7/8. AZT dose dependently increased secretion of IL-8 and CCL3, whereas levels of these cytokines were decreased by tenofovir DF (Figs. 2A, B). To assess whether tenofovir DF and AZT directly affect IL-8 transcription or RNA stability, we pretreated cells with tenofovir DF or AZT for 1 hour before stimulation with TNF-α. After 5 hours, total RNA was harvested and IL-8 mRNA was determined using real-time PCR. AZT did not affect IL-8 mRNA levels (Fig. 2C). In contrast, tenofovir DF decreased IL-8 mRNA levels after TNF-α stimulation, suggesting that tenofovir DF may exert its suppression partly at regulating RNA levels. Because IL-8 is transcriptionally regulated by the transcription factor NF-κB,48 we assessed whether NF-κB activation is directly affected by tenofovir DF. As illustrated in Figures 2D-F, neither AZT nor tenofovir DF directly affected NF-κB activation after TNF-α stimulation, thus suggesting that tenofovir's regulatory role is independent of interference with signaling, leading to cytokine production.
To assay the effect of tenofovir DF and AZT on early cytokine responses during secondary infections, cells were infected with S. pneumoniae, N. meningitidis, E. Coli, or CMV in the presence or absence of tenofovir DF or AZT. As observed in Figures 3A-C, AZT enhanced IL-8 and CCL3 responses, whereas tenofovir DF reduced pathogen-induced cytokine secretion. Similar results were obtained in the monocytic cell line THP-1 (see Figure, Supplemental Digital Content 1,http://links.lww.com/QAI/A158). We next performed similar experiments in human primary PBMCs. Like U937 cells and THP-1 cells, PBMCs were inhibited in their ability to produce CCL3 in the presence of tenofovir DF (Figs. 3D, E). In contrast, TLR-induced and pathogen-induced IL-6 levels were only slightly affected or unaffected by the presence of tenofovir DF (Figs. 3F, G). In conclusion, early innate immune response to bacterial and virus infections is inversely affected by tenofovir DF and AZT in monocytes, whereas tenofovir DF affects cytokine production selectively in human PBMCs.
Because IL-12 is an important regulator of cell-mediated immunity controlling infections, and the fact that HIV-1 infection reduces levels of IL-12 and upregulates levels of IL-10,35,39,41 we evaluated the effect of tenofovir DF and AZT on IL-10 and IL-12 in human cells. After infections with live bacteria, TLR stimulation or stimulation with TNF-α, IL-10 levels were strongly reduced in the presence of tenofovir DF, whereas AZT did not affect IL-10 secretion (Figs. 4A-C). In contrast, tenofovir DF strongly enhanced IL-12 secretion after pathogen infection and TLR stimulation (Figs. 4E-G). Similarly, tenofovir DF decreased IL-10 mRNA accumulation and increased IL-12p40 mRNA accumulation after TLR triggering (Figs. 4D, H, respectively), thus suggesting a regulatory role at the level of RNA regulation. In conclusion, tenofovir DF affects the IL-12/IL-10 balance during infection and inflammation.
Because mRNA accumulation of IL-10 and IL-12 was affected by tenofovir DF (Figs. 4D, E), we evaluated the role of tenofovir DF on signaling pathways regulating cytokine production. Tenofovir DF did not affect NF-κB signaling after TNF-α stimulation and only slightly affected LPS-induced NF-κB activation (Fig. 5A). The protease inhibitor saquinavir, known to interfere with the proteasome and NF-κB activation after LPS stimulation,10 inhibited LPS-induced NF-κB modestly. To determine whether tenofovir DF affects MAPK signaling, we assayed whole blood stimulated with LPS in the presence or absence of tenofovir DF or the MAPK inhibitor U0126. As illustrated in Figure 5B, no change in activation profiles for ERK or p38 MAPK was seen in the presence of tenofovir DF, whereas the inhibitor U0126 strongly inhibited ERK phosphorylation after LPS stimulation. In conclusion, tenofovir DF does not strongly affect MAPK or NF-κB activation in human primary cells.
In this study, we have investigated the effects of the often used NRTIs tenofovir and AZT with respect to their ability to affect cytokine production from human cells during infections, after inflammatory stimuli and TLR stimulation. Tenofovir decreased and AZT increased both IL-8 and CCL3 production from monocytes after stimulation with TLR ligands, TNF-α, or live pathogens (Fig. 1-3). Similarly, tenofovir decreased CCL3 levels in human PBMCs (Figs. 3D, E). AZT did not affect cytokine induction in PBMCs (Figs. 3, 4). Although the presence of tenofovir DF reduced levels of TNF-α-induced IL-8 mRNA (Fig. 2C), the inhibition of mRNA accumulation was not linked to direct interference with signaling essential for cytokine transcription because neither tenofovir DF nor AZT affected NF-κB activation in U937 cells (Fig. 2D). For AZT, our findings are in agreement with the report from Kurata15 observing no significant NF-κB activation in U937 cells at early time points 3-5 hours after AZT treatment.
In contrast to our results, previous studies have shown that tenofovir directly promotes expression of cytokines in murine (peritoneal macrophages) and human cells (U937 cells and PBMCs).7,12,13 Based on the previous findings, we were surprised not to observe any tenofovir-induced cytokine expression (IL-8, CCL3, IL-12, IL-10, or IL-6) neither in U937 cells nor in human PBMCs (Figs. 1-4). To make sure that the preparation of drug did not affect the outcome, we included tenofovir DF from solubilized drug (Viread) and tenofovir in the processed form, which was used in the studies showing cytokine induction by tenofovir. No inducing effect was observed (Figs. 1A, B). We cannot explain the discrepancy in results gained. However, having tested 2 sources of prodrug tenofovir (tenofovir DF) obtaining similar results, our data strongly suggest that, at least in the model systems used in our experiments, tenofovir is not by itself an efficient cytokine inducer. Rather, tenofovir DF is a selective negative regulator of inflammatory cytokines.
IL-10 and IL-12 are pivotal cytokines in regulating immune responses. IL-10 is a potent inhibitor of inflammation and immune responses to infections and antigens.36,37 HIV infection results in increased levels of IL-10 in monocytes and CD4+ and CD8+ T cells.39,41 Tenofovir DF pretreatment of human PBMCs reduced levels of IL-10 when challenged with the inflammatory cytokine TNF-α, TLR ligands, or live bacteria (Figs. 4A-D). Investigation of human PBMCs and whole blood confirmed that tenofovir DF is neither a strong agonist nor antagonist of MAPK or NF-κB signaling (Figs. 5A, B). Collectively, the data suggest that the tenofovir DF-mediated changes in cytokine profiles are not mediated through changes of intracellular signaling activity via NF-κB or MAPK pathways.
Whether decreased production of IL-10 is linked to an improved clinical prognosis remains to be determined. IL-12 plays an essential role in regulating cell-mediated immunity controlling both HIV and secondary infections.29,30 Decreased levels of IL-12 have been associated with increasing HIV disease severity and faster progression to AIDS.32,33 We found that tenofovir DF strongly enhanced PBMC's ability to respond with IL-12 after infection with live bacteria or stimulation with TLR ligands (Figs. 4E-H). Our findings are in line with studies from macaques showing that tenofovir primes PBMCs for IL-12 secretion.49 Knowing that IL-12 administration to PBMCs from patients with HIV restores the cell's immune capability,50-53 it is tempting to speculate that tenofovir could improve the general immune response to secondary infection and possibly also prime the immune response against HIV antigens.
Recently, the Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 study showed that tenofovir as a microbicide provides protection against HIV-1.54 One of the pivotal characteristics of microbicides is their ability to preserve mucosal immune function and not induce inflammation.55 The present study, describing tenofovir's ability to reduce releases of inflammatory mediators, including chemokines IL-8 and CCL3 (Figs. 1-3), may play a part in tenofovir microbicide gel's protective effect. Inhibited inflammation may reduce the influx of potential host cells for HIV-1 and reduce inflammatory tissue damage. Interestingly, the CAPRISA 004 study also found that tenofovir decreased acquisition of herpes simplex virus (HSV-2) but not via a direct antiviral effect.56 Supporting the assumption that tenofovir does not possess strong direct antiviral effect against HSV-2, no decreases in HSV-2 shedding are observed in patients receiving oral tenofovir DF.57 One might speculate that regulation of cytokine networks by tenofovir could prime the host for a better anti-HSV-2 response. Although we demonstrate that tenofovir primes human cells for decreased inflammatory responses and enhanced IL-12 secretion after a secondary stimulus, it is very difficult to extrapolate the effects to human diseases. One reason is the fact that the plasma drug concentration in patients is lower than the concentrations used in the in vitro studies (most often 1-100 μM). As an example, the maximum concentration of tenofovir in plasma after administration of 1 dose of tenofovir DF (Viread, 300 mg) is approximately 300 μg/L,58 which corresponds to approximately 1 μM. Further studies will have to delineate the in vivo effect of tenofovir on inflammation and acquiring secondary/opportunistic infections.
In summary, our results provide data on tenofovir's immune modulatory effect. Tenofovir selectively affects levels of secreted inflammatory cytokines and shifts the IL-10/IL-12 balance after cell stimulation with TLR ligands or infection with live bacteria. Collectively, our data suggest that the choice of NRTI may affect overall inflammation and early immune responses against secondary pathogens.
Pure compounds of AZT, tenofovir, tenofovir DF, abacavir, and saquinavir were obtained from the AIDS Reagent and Reference Reagent Program, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.
tenofovir; pathogen; IL-12; IL-10; inflammation; microbicide
© 2011 Lippincott Williams & Wilkins, Inc.
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text: Rajon Rondo is in Paris promoting Nike Basketball at the Nike World Basketball Festival. The Celtic's point guard has been sponsored by Nike since 2009. Rondo sat in on a question and answer session about the new Nike Hyperdunk+. The revolutionary Nike Hyperdunk+ men's basketball shoe tracks every move of your game and syncs directly to your mobile device, letting you know exactly how high, how quick and how hard you play. Your progress is rewarded. Nike+ sensors measure your vertical, quickness and hustle. The Nike+ app lets you share and compare your stats and video. These high tech shoes feature Lunarlon and Flywire technologies which combine for exceptional cushioning and support. This shoe and technology is a game changer for basketball players. The shoes mix traditional training with a video game. What do you think of the high tech basketball kicks?

subset: commoncrawl


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text:
Hyrule Warriors will be getting two special editions in Japan, called the Premium Box and the Treasure Box. These special edition boxed sets will include the above Triforce clock, revealed by Tecmo Koei to Zelda Informer. The Premium Box will have an official booklet and six character costumes in addition to the game and the clock.
The Treasure Box will contain the game, official booklet, clock, eight character costumes, the scarf Link wears in the game and a treasure box that emits sound. Treasure Box pre-orders are limited to Amazon Japan and Game City, while the Premium Box is currently available for ordering on Play Asia if you wanted to import it to receive this fancy collector's edition.
There's no word on whether any of these goodies will be making it Stateside, but you can color us green with envy. Be sure and check out our footage of Hyrule Warriors from E3.
Continue reading:
- Nintendo: Switch is a new platform, not a suc
- WiiUDaily's Big Switch
- Rumored Nintendo Switch specs reveal a pretty
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TAGS: hyrule warriors, Nintendo, Triforce, wii u


text:
Donate Fur Coats to be Used with Wildlife
Many people find themselves in possession of a fur coat that they do not want. They may have decided to stop wearing fur, or they may have inherited a relative's coat. Sometimes the coat is faux fur and is simply not needed any more. Whatever the reason or source, many of these people would like to find a way to dispose of the coat in a productive manner.
You are welcome to send your furs to HSUS. Through our Give Fur Back
to the Animals program, we collect all types of real or faux fur and
donate them to wildlife rehabilitators all around the country who use
the fur as bedding with their orphaned or injured wildlife.
Donating is easy. Simply pack up the fur in a sturdy box and mail to:
2100 L. St. NW
Washington, DC 20037
attn: Fur Free Century
and make sure to include your full name and address so I can mail you
a thank you later that you may use as a receipt for claiming a tax
For more information on the program and claiming a tax deduction, see
http://www.hsus.org/ace/12024 Please do not hesitate to call or email me with further questions.
I have available a few pictures that wildlife rehabbers have taken of
wildlife using the donated fur.
Andrea Cimino
Campaign Manager, Wildlife and Habitat Section
The Humane Society of the United States
2100 L St. NW
Washington, DC 20037
Posted on SHARE Yahoo group Apr 20, 2004


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Increasing reuse no longer applies to just large automated test systems. Electronic design and validation engineers are experiencing similar needs for improved productivity through increased measurement efficiency and reuse in the lab. One of the key factors driving the need for increased productivity in the lab is the rising complexity of today's electronic devices. The rapid growth in device functionality results in longer design verification and validation cycles that often cause delays in new product introductions or result in poor design quality.
While design and test engineers share a similar need for test reuse in the lab and on the production floor, their means for achieving increased reuse differ. Reuse in automated test typically involves maximizing the investment in software development efforts and measurement hardware. It is difficult for design engineers to measure themselves exactly by these guidelines because the majority of their time is spent adjusting knobs and dials on benchtop instruments and recording measurements rather than programming test code. Thus, design engineers should focus their attention on how they can perform more measurements in a shorter amount of time to maximize their use of lab time.
Improving measurement efficiency in the lab begins with identifying aspects of the design verification and validation process that consume the most time. This includes tracking time spent on repeated measurements, correlating measurement signals, programming instrument control applications, and reconfiguring shared instruments. Next, design engineers can apply new tools, such as National Instruments SignalExpress software, to reduce greatly the time spent in each of these areas.
NI SignalExpress is an interactive measurement environment for performing ad hoc and automated measurements in the lab. Using SignalExpress, design engineers can control multiple instruments and perform a variety of measurements from a single software user interface. In addition to performing single measurements, engineers can save instrument configurations and measurement routines for repeated measurements as SignalExpress projects that they can easily reuse. Engineers also can use SignalExpress to quickly correlate signals acquired from multiple devices or channels on a given device. They can import simulated results from SPICE software tools for side-by-side correlation with measured results. The SignalExpress sweeping and limit test operations also save engineers time when they perform stimulus and response measurements across a range of frequency, voltage, or current settings.
Design engineers can greatly increase measurement reuse and productivity in the lab by identifying the major bottlenecks and applying measurement automation tools such as NI SignalExpress. To learn more about SignalExpress, visit http://rbi.ims.ca/3860-539.


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To the editor:
Many years ago (just after the 1980 Olympics), I brought my two young sons to Placid for a week of cross-country skiing, downhill skiing and ice skating. It was great, and they fell in bed at night as if dead. It was, as both of them now put it, "our best vacation ever."
Just this past week, I brought the mother of those two boys to Placid for her first intro. (She fell in love with the area). We skied and skated again, and climbed to the top of the bobsled track to watch the "Worlds" (wow!), and I noticed some articles about doing a "rail to trail" in the Placid area and some controversy surrounding the proposal.
Perhaps my experience here can help. I was the Tioga County (Pa.) planner in 1990, when we had our first rail-to-trail proposal. I sat in all the meetings and, in fact, ran some of them. Again, there was much controversy over railroads, private property rights, etc. We went through some years of those meetings with the Pennsylvania state forestry department (which owned much of the land) and private land owners (who were also stakeholders).
There were fears, including for property rights, giving up the rail (although it was only banked for the future) and basically what kind of folks would be using it and would they be a threat to our local, rural way of life. Believe me, you in the Placid area have seen much more influx from outsiders than we ever had. I believe the rail use was not even close to the issue of who would be on that trail and would they respect our beautiful Pine Creek Canyon (called the Grand Canyon of Pennsylvania).
In short, that rail-to-trail, all 62 or so miles of it, has been running great for a number of years now, with only small problems and as a great resource to many, both local and non. The economic benefits have been well documented here. I hope you folks can work it out. It will only add to your community.
P.S.: That trail now hooks up to one in the Susquehanna Valley, and can get you all the way to D.C.
Kerry Gyekis
Former planner, present-day private consultant, forester and writer for www.theforester.com
Morris, Pa.


text: .\"*************************************************************************** .\" Copyright (c) 2000-2005,2007 Free Software Foundation, Inc. * .\" * .\" Permission is hereby granted, free of charge, to any person obtaining a * .\" copy of this software and associated documentation files (the * .\" "Software"), to deal in the Software without restriction, including * .\" without limitation the rights to use, copy, modify, merge, publish, * .\" distribute, distribute with modifications, sublicense, and/or sell * .\" copies of the Software, and to permit persons to whom the Software is * .\" furnished to do so, subject to the following conditions: * .\" * .\" The above copyright notice and this permission notice shall be included * .\" in all copies or substantial portions of the Software. * .\" * .\" THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS * .\" OR IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF * .\" MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. * .\" IN NO EVENT SHALL THE ABOVE COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, * .\" DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR * .\" OTHERWISE, ARISING FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR * .\" THE USE OR OTHER DEALINGS IN THE SOFTWARE. * .\" * .\" Except as contained in this notice, the name(s) of the above copyright * .\" holders shall not be used in advertising or otherwise to promote the * .\" sale, use or other dealings in this Software without prior written * .\" authorization. * .\"*************************************************************************** .\" .\" $Id: curs_trace.3x,v 1.8 2007/02/24 17:33:49 tom Exp $ .TH curs_trace 3X "" .na .hy 0 .SH NAME \fB_tracef\fR, \fB_tracedump\fR, \fB_traceattr\fR, \fB_traceattr2\fR, \fB_nc_tracebits\fR, \fB_tracechar\fR, \fB_tracechtype\fR, \fB_tracechtype2\fR, \fB_tracemouse\fR, \fBtrace\fR - \fBcurses\fR debugging routines .ad .hy .SH SYNOPSIS \fB#include <curses.h>\fR .sp \fBvoid _tracef(const char *format, ...);\fR .br \fBvoid _tracedump(const char *label, WINDOW *win);\fR .br \fBchar *_traceattr(attr_t attr);\fR .br \fBchar *_traceattr2(int buffer, chtype ch);\fR .br \fBchar *_nc_tracebits(void);\fR .br \fBchar *_tracechar(int);\fR .br \fBchar *_tracechtype(chtype ch);\fR .br \fBchar *_tracechtype2(int buffer, chtype ch);\fR .br \fBchar *_tracemouse(const MEVENT *event);\fR .br \fBvoid trace(const unsigned int param);\fR .SH DESCRIPTION The \fBtrace\fR routines are used for debugging the ncurses libraries, as well as applications which use the ncurses libraries. These functions are normally available only with the debugging library \fIlibncurses_g.a\fR, but may be compiled into any model (shared, static, profile) by defining the symbol \fBTRACE\fR. .PP The principal parts of this interface are the \fBtrace\fR routine which selectively enables different tracing features, and the \fB_tracef\fR routine which writes formatted data to the \fItrace\fR file. .PP Calling \fBtrace\fR with a nonzero parameter opens the file \fBtrace\fR in the current directory for output. The parameter is formed by OR'ing values from the list of \fBTRACE_\fP\fIxxx\fR definitions in \fB<curses.h>\fR. These include: .TP 5 TRACE_DISABLE turn off tracing. .TP 5 TRACE_TIMES trace user and system times of updates. .TP 5 TRACE_TPUTS trace tputs calls. .TP 5 TRACE_UPDATE trace update actions, old & new screens. .TP 5 TRACE_MOVE trace cursor movement and scrolling. .TP 5 TRACE_CHARPUT trace all character outputs. .TP 5 TRACE_ORDINARY trace all update actions. The old and new screen contents are written to the trace file for each refresh. .TP 5 TRACE_CALLS trace all curses calls. The parameters for each call are traced, as well as return values. .TP 5 TRACE_VIRTPUT trace virtual character puts, i.e., calls to \fBaddch\fR. .TP 5 TRACE_IEVENT trace low-level input processing, including timeouts. .TP 5 TRACE_BITS trace state of TTY control bits. .TP 5 TRACE_ICALLS trace internal/nested calls. .TP 5 TRACE_CCALLS trace per-character calls. .TP 5 TRACE_DATABASE trace read/write of terminfo/termcap data. .TP 5 TRACE_ATTRS trace changes to video attributes and colors. .TP 5 TRACE_MAXIMUM maximum trace level, enables all of the separate trace features. .PP Some tracing features are enabled whenever the \fBtrace\fR parameter is nonzero. Some features overlap. The specific names are used as a guideline. .SH RETURN VALUE Routines which return a value are designed to be used as parameters to the \fB_tracef\fR routine. .SH PORTABILITY These functions are not part of the XSI interface. Some other curses implementations are known to have similar, undocumented features, but they are not compatible with ncurses. .SH SEE ALSO \fBcurses\fR(3X). .\"# .\"# The following sets edit modes for GNU EMACS .\"# Local Variables: .\"# mode:nroff .\"# fill-column:79 .\"# End:


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An ice storm warning was issued Friday night for northern Lower Michigan, in effect through 1 a.m. Saturday.
The ice storm warning affects from Gladwin and Arenac Counties north to the Mackinac Bridge.
Bay County and Midland County are under a freezing rain advisory Friday night, expiring 1 a.m. Saturday.
In the ice storm warning area, which includes Standish, Gladwin, Traverse City, Gaylord, and Alpena, one-quarter of an inch of ice could accumulate on untreated roads. Temperatures should then start to warm above freezing, and some melting will occur.
In Bay and Midland Counties, one-tenth to one-quarter of an inch of ice could accumulate on colder road surfaces. Bridges and overpasses would be additional areas that could have icing.
The freezing rain in Bay and Midland Counties is expected to change to rain overnight, as temperatures warm.
Travel on Saturday morning should be better, with temperatures in the mid to upper 30s melting much of the ice.
This does not look like a situation that is long lasting or will create large power outages. As the temperatures warm overnight, icing on road surfaces will melt off.
For the overnight hours just use extreme caution if you are going to be driving in the northern third of Lower Michigan or anywhere in the U.P.
Post your road report here
Once you are safe at home, post the road conditions you encountered below.
Mark Torregrossa has been the chief meteorologist for three television news stations in Michigan. A resident of the state for 20 years, he has also gardened since the age of ten and is an avid hunter. Email him at firstname.lastname@example.com and find him on Facebook at facebook.com/mark.torregrossa and Twitter @weathermanmark


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HUNTSVILLE, Alabama _ Spending a year out of work and all the problems that ensued because of it have taken something of a toll on me. I am thankful to be working again, but like a majority of Alabamians who have gone through or are going through this, I'll bet that the situation is not ideal.
I know for myself that is the case. I think that being jobless for so long has caused some fundamental changes in my personality. For starters, I save a lot more money than I used to. I have always been a saver. My parents taught me the value of a dollar, but I put a lot more of them away than I used to. I keep spare change for more rainy days, and I will pick up pennies from parking lots because it all adds up.
I'm not nearly as optimistic as I once was. To paraphrase, "I stare into the abyss... and all I see is a deep dark hole with no end in sight." I have become a fervent believer in preparing for the worst and expecting the worst. I guess it was all the rejections.
I put in a rather large number of job applications. Just ball park, I think 95 to 98 percent of them were rejected or ignored totally. It just gets you down after awhile and you question your value as a person.
Trust is an even bigger issue for me than ever before, because of certain, shall we say, "situations" that I have dealt with in the past. I live by the mantra "trust...but verify," meaning that I wait until the other person commits themselves before I believe anything that they are promising me.
I deal in truth whether it is pleasant truth or unpleasant truth. The saying, "My word is my bond," means a lot to me. I also tend to look for the clouds in the sunny sky; I guess I almost reflexively wait for the other shoe to drop as it has happened so often recently.
It could be that I might have experienced more career reversals than the average person, or it my have something to do with my outlook on life at the moment, but I don't take the rosy view that I once had in regard to life.
I loathe spending money, even for the things I need. Some would charitably call me a cheapskate and they would be right. When I decide to buy anything, the first thing that I think of is, do I really need this, and how do I get it cheaper.
To put it another way, what I want and what I need are two entirely different things and if moneywise they don't match up then I don't buy it.
I am constantly reminding myself that I have a job and if I want a new DVD then I can get it, or If I want to go out to eat I can because I don't have to worry about spending the majority of my unemployment check.
I can let my gas tank go lower than a fourth from a full tank because I know I will have money to fill it up again. I decided to finally buy something nice for myself, the aforementioned iPad from last month's article. Even then it is a first generation iPad not an iPad 2. I got it for significantly less than the normal retail price and it took me the better part of a month just to make the decision to actually buy it. Then another three weeks to pull the trigger on the purchase.
I must have a bit of the optimist that I used to be left, so I want to offer some hope. If you are still unemployed, keep seeking; you will find a job.
If the job is not what you really want, be thankful you found it, and be willing to help those truly less fortunate than you. Once again people, don't sit on information, share what you know; knowledge kept and not shared is knowledge wasted.
Jovan Coates is a 2011 Times community columnist.


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The Euclid Creek Stream Cleanup Event, held each fall and spring, takes place Saturday from 10 a.m. to noon at Wildwood State Park. Ambitious volunteers can arrive an hour early to learn about and help maintain the park's bioswale. Stream cleanup volunteers should gather at the parking lot nearest the entrance, located off East 174th Street and Lakeshore Boulevard; whereas bioswale volunteers should proceed to the well-marked marina lot at 9 a.m. Volunteers under 18 must be accompanied by an adult.
Volunteers should dress for the weather and wear sturdy boots or shoes, as well as long sleeves and pants. Trash bags and work gloves are provided, though volunteers are encouraged to bring their own gloves to ensure an ample supply.
Registration is not necessary, though Claire Posius of the Cuyahoga Soil and Water Conservation District, the group that organizes the cleanup, says she hopes to have a rough estimate of the number of people planning to attend. Posius can be reached at 216-524-6580, ext. 16.
Posius, the Euclid Creek watershed coordinator, reveals that several groups are co-sponsoring the cleanup. The soil and water conservation district, Friends of Euclid Creek, the Euclid Creek Watershed Council, Cleveland Lakefront State Parks, the Cleveland Water Pollution Control Division and the Northeast Ohio Regional Sewer District are all contributing in some way. In addition, Radio One is supplying free event promotion.
Posius explains that the cleanups not only provide a way for residents to get involved, but also act as an educational forum. At the beginning of the event, Posius will discuss behaviors that result in the need for regular cleanups. Posius emphasizes that all residents should be aware that storm sewers drain directly to the creek.
Posius also plans to offer information about Wildwood's bioswale, which was constructed in 2009. The bioswale is a depression that captures and filters runoff from the impermeable asphalt parking lot. Native plants further help to remove pollutants. As a lowland area, the bioswale attracts significant amounts of litter. The Friends of Euclid Creek regularly maintains the area by clearing debris and pulling weeds, though events like the one on Saturday allow much more to be accomplished.
The spring 2013 cleanup at Wildwood includes an invasive plant pull and persons seeking further volunteer opportunities may be interested in upcoming wetland planting activities. Major construction of Wildwood's restored wetland areas will conclude near the end of 2012, but many volunteers are needed to help harvest and plant native species. Interested parties should contact Posius for details.
As one of the most accessible and highly used parks along the Cleveland shoreline, Wildwood State Park contends with regular litter accumulation. However, problems plaguing the largely urban 23-square-mile Euclid Creek watershed include not only litter, but also chemical and organic pollutants and erosion. Residents can help to remedy such problems through simple steps like cleaning up pet waste, limiting applications of chemicals and fertilizers and installing rain barrels.


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The Titans won't have many options at the QB spot if Kerry Collins does not come back to the team in 2009, as they are clearly counting on his return. Today's Nashville City Paper says that the team thinks that Collins will be back:
As for Kerry Collins, who has said he wants to return as the starter, the Titans are still banking that he will return, though nothing is imminent at the present time. "We said at the end of the season that we had hope and expectation that we would be able to re-sign Kerry," Fisher said "I also said that Vince [Young] is eventually going to be our starter. So, we don't know what the market's going to be. I believe that Kerry has every intention of coming back. And if he comes back, for all intents and purposes, he's our starter, and Vince waits. If he doesn't, then we'll deal with that, but our interest right now is to try and get Kerry back." The Titans are also trying to re-sign Chris Simms, who was their third-string quarterback last year.


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When it was over, when SU disposed of Maine 101-55 inside the Carrier Dome, the Orange had converted 12 of the 23 3-pointers it attempted. That's 52.2 percent. The performance boosted SU's overall 3-point shooting percentage to 42 percent thus far this young season.
SU, it seems, can bury the ball from the perimeter.
"I think it's the ball movement," said SU guard Andy Rautins (2-of-4 from 3). "I mean, we're getting really good looks out there. We're going high post, low post, kicking it out. Definitely easy buckets in transition too."
"Everybody can shoot the ball," said SU guard Mookie Jones (4-for-7 from 3). "I think we've been moving the ball around, we've been unselfish. And I think everyone is confident. If you're confident, you're going to knock down those shots."
The Orange guards point to the respect that defenses pay to Rick Jackson and Arinze Onuaku as part of the reason they have been allowed open shooting areas on the perimeter. Maine clearly wanted to concentrate on defending the interior on Saturday night. That left wide open patches of shooting space for SU to exploit.
Still, a 3-point basket looms at least 20 feet, 9 inches away. The Orange shot 34.5 percent from 3-point range overall last season and 36 percent during Big East play.
So far, this year's team has easily eclipsed those numbers. The Orange started Saturday's game tied with Georgetown for the Big East's best 3-point field goal percentage at 40.5. SU is now making 42 percent of its 3-pointers. The Orange's best 3-point shooting team all-time was the 1986-87 edition, which shot 40.3 percent from long distance. That year's team attempted just 248 3-pointers.
This year, SU is already 74-of-176. Against the Black Bears, six Orange men made at least one 3-pointer.
"Overall, we can shoot," Triche (2-of-2) said. "Coming into the season, I thought we would be more of a 3-point shooting team, actually. Playing pickup with the guys, I saw that Wes could shoot. Andy. Mookie, Kris. I can shoot it a little bit. I could see all our forwards can shoot it and the 2-guards, too."
"The 3s have really been working for us," Jones said. "Everybody's been working on it. And everyone's been really hitting. That's been great for us."
Concentration – SU led by 48 points at half time. And yet, protocol dictated the Orange return for the final 20 minutes.
So what was discussed in the SU locker room at halftime? What kind of second-half goals did the Orange set?
"Not to have any mental lapses out there. You don't want to pick up any bad habits in the second half," Rautins said. "You want to finish the game on a strong note. You don't want to get sloppy."
"Coach, he's the best at still motivating us no matter what the score is out there," SU guard Scoop Jardine said. "Don't let up. We went back out there like it was 0-0. We're trying to get better every game. We're trying to come out here and be focused, no matter what game it is. We call it 'little victories' that we're trying to get better every game."
The SU players, too, said the switch to man defense to start the half gave them something else to think about. And Rick Jackson was honest enough to admit that as a starter, he has his own strategy in blowout wins.
"You know you're not going to be out there for long," he said, "so you just want to do your job, get the job done, stay on top. Don't give up stupid buckets and just work on some things."
Rebound – SU, which came into Saturday's game ranked 14th among 16 Big East teams in rebound margin (plus-2.1), put some distance between itself and the Black Bears on the boards.
The Orange outrebounded Maine, 45-33. Jackson led the Orange with eight boards in 24 minutes. Arinze Onuaku collected seven missed shots in 19 minutes. Granted, the numbers came against smaller Maine. But the Orange needed a dominating performance on the glass.
"We gotta just go after every one," Jackson said. "Everybody wants to score, so why not get the rebound? As far as defensive rebounds, you don't want to let a guy get a rebound and get a second chance to get a bucket. Just don't make sense to me."
Jackson was asked why SU has struggled on the backboards thus far this year. He echoed what Onuaku said a couple weeks ago: "We play zone. When you play zone you give up a couple rebounds because you can't really block out. If we played man, I think we'd get more rebounds. But zone is our strongest point on defense."
Scoreboard malfunction -- The scoreboard that usually rests behind the pull-out bleachers opposite the team benches at the Carrier Dome was missing Saturday night. That made it difficult for fans sitting behind the benches to see the running tally of scoring and fouls for Syracuse and Maine players.
Rob Edson, SU's senior associate athletics director, said the hydraulic lift that raises the scoreboard had broken. Dome personnel had hoped to repair the lift by game time Saturday, but when that didn't happen, a decision was made to remove the scoreboard entirely.
"It's a function of safety," said Edson, who added he expected the scoreboard to be repaired and working by SU's next home game – Dec. 13 vs. St. Francis.
Contact Donna Ditota at 470-2208 or email@example.com.


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It was the first shot in a battle that will decide whether Chris Christie's second term is a success or a failure.
On Tuesday, state Sen. Kevin O'Toole put out a news release calling for an end to what he termed the "filibuster" of the governor's nominations to the state Supreme Court. As a remedy, the Essex County Republican is sponsoring a resolution that would require all Supreme Court nominations be put up for a vote within 90 days.
There are two flaws in O'Toole's argument. The first is that the Democrats in the state Senate have no need to filibuster. The word "filibuster" describes a tactic by which legislative minorities talk something to death. But the Democrats have a 24-16 majority in the Senate. They don't need to talk.
That leads to the second problem. If the Republicans had enough votes to pass this bill, they wouldn't need it. They'd just confirm the two nominees who've been refused hearings by the Democrats.
O'Toole's not dumb. In fact, he's one of the sharper members of the Senate. He's also Christie's right-hand man there. So just what is he up to?
"At some point somebody has to blink," O'Toole told me. "We can't just have this constitutional crisis go on forever."
The crisis in question traces to May 2010, when the new governor refused to renominate Associate Justice John Wallace to the high court. That enraged Wallace's fellow Democrat and fellow resident of Gloucester County, Senate President Steve Sweeney. Sweeney has left that seat open ever since. He has permitted Christie to fill two other seats on the court, but he refuses to even hold hearings on another two nominees.
Two and two make four. And that would represent a majority on the seven-member court, which has a reputation as one of the most liberal and most activist in the nation.
Christie has been promising since his first campaign in 2009 to change the makeup of that court. So what will he do?
He could take a hint from the Democrats in the U.S. Senate. Recently they voted to end a real filibuster, the tactic employed by the Republican minority that was keeping the Democrats from confirming President Obama's nominees to the appellate courts.
Beltway Republicans complained about this. But that's what losers do: complain. Christie has a reputation as a winner. And winners impose their will upon their opponents.
If the governor wants to win, there's a simple tactic available to him, one that has been explored in some detail by Ed Hartnett, a professor at Christie's old law school. The Seton Hall scholar's research reveals it would be a relatively simple matter for Christie to name two judges to the high court during the Senate recess that will occur next month between sessions.
Will he make those recess appointments? Perhaps. But perhaps he has something else in mind.
That might involve the biggest decision Christie will face in his second term. In June, the governor has to decide whether to reappoint Chief Justice Stuart Rabner to the court.
When asked in 2009 whether any of the judges then on the court met his standards, Christie said no, saying he wanted "someone who will interpret laws and the Constitution, not legislate from the bench." So that makes it sound like Rabner will be back in private practice by July.
But there are rumors among Republicans to the effect that Christie might be willing to make a deal to reappoint his former subordinate at the U.S. Attorney's Office to the court. In return he would get his other two nominees confirmed.
If that were to happen, Christie would be following in a Republican tradition that got the GOP into this mess. The prior three Republican governors either appointed or reappointed liberal activist chief justices. The result was not just some of the most activist decisions on Earth, but also the legislative redistricting plans that appear to doom the Republicans to minority status in the Legislature until at least 2020.
That's when whoever is chief justice will get to pick the tie-breaker in the next redistricting. So the Republicans have a lot riding on this.
As for the highest-ranking Republican, he will have ridden into the sunset by then, and perhaps into the White House.
As O'Toole said, someone has to blink. But before you can blink, you have to open your eyes. So far, the Trenton Republicans haven't fared well in that regard.


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WANTAGE -- The owner of a small airport in Sussex County who admitted embezzling from Federal Aviation Administration was ordered by a federal judge today to serve two years of probation and repay $372,000 to the government.
Paul G. Styger, 87, who has owned Sussex Airport since 1953, admitted in May 2009 that he pocketed money intended for upgrading the runway, airfield and other facilities.
He faced between 18 and 24 months in prison under the terms of his plea deal. His attorney, Henry E. Klingeman, said Styger was grateful to Federal District Judge Jose Linares for sparing him from prison and recognizing his positive contributions to society.
Beginning in 2004, Styger applied for six FAA grants and received about $3.1 million. He used some of that money to pay for improvements at the Wantage airport, then began embezzling in 2007, authorities said. In 2008, a construction firm sued Styger in state Superior Court, claiming it was never paid for $539,000 worth of work on the runway.
His airport hosted the annual Sussex Air Show until 2004. At the time, Styger said the 32-year tradition attracted about 25,000 people and was dubbed "the Biggest Little Air Show in the East."


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Washington Township's 2012 budget has received approval from the New Jersey Division of Local Government Services, Mayor Barbara Wallace announced Wednesday.
The budget amendment presented to the state provided for a $285,000 spending reduction to the original $35 million budget proposal. It would result in a tax rate increase for the owner of a home assessed at the township average of $130,000 to about $12 a year.
The budget Wallace originally proposed last month included a tax rate increase of about $26 a year.
"I am pleased that the division has approved our budget, along with the recently introduced amendment," said Wallace. "This now means that we can move forward with our capital and roads program, while still spending over a million dollars less than last year."
The savings in the amended budget would come from the combination of the $6.9 million bond that would fund the capital improvement plan into a short-term bond anticipation notice, or BAN, that the township was issued in the past.
If the township approves the $6.9 million long-term bond for the capital improvement plan and rolls the BAN—which is due to be converted to long-term financing in the next few years regardless—into it, they do not have to pay the BAN's $285,000 principal payment this fall.
That savings will be used to offset the $350,000 down payment for the capital plan bond that is included in this year's budget and thus decrease the tax levy.
Wallace said the council will be asked on May 23 to approve the bond ordinance and the capital improvement plan.
"By adopting the capital ordinance, we can provide much needed relief to our deteriorating infrastructure and lower taxes over original estimates," Wallace said. "I ask that the council move swiftly now that we have the green light from the state."
New Jersey law establishes a three-year rotating comprehensive review process of municipal budgets, explained Wallace. This budget year, Washington Township underwent the comprehensive review.
"Although the state looks closely at the entire budget, much of the focus is on ensuring accuracy of revenues and appropriations and on legal compliance," said Wallace.


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Binghamton, NY (WBNG Binghamton) Seven jurors and three alternates were selected in Broome County Court Friday for the double murder trial of Aaron Powell.
Five jurors were seated on Thursday, totaling twelve jurors and three alternates.
Aaron Powell is facing two charges of murder in the second degree, and one count murder in the first degree.
He's accused of killing his estranged wife Christina Powell, 35, and her friend, Mario Masciarelli, 24.
Judge Joseph Cawley along with defense and prosecution attorneys agreed on 11 jurors between yesterday and this morning but they exhausted the first jury pool and had to summon an 20 additional people this afternoon.
District Attorney Gerald Mollen and Defense Attorney Tom Kline asked the jurors questions relating to their personal history, if they watch crime shows on TV and whether it bothered them that Powell wasn't in the courtroom for jury selection.
12 jurors and three alternates were selected to hear the case.
Opening arguments in Aaron Powell's trial will begin Monday morning.


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Your little socialite will drool over the Sophia Party Dress from Pooch Outfitters!
- Velvety party dress with faux-pearl necklace, bow, pom poms, and crystal buckle.
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What We Love About It:
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X-Small: 7.25
Small: 8.5
Medium: 11.5
Large: 13
X-Large: 16
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X-Small: 12"
Small: 14"
Medium: 16.5"
Large: 19"
X-Large: 22"
|Neck Dimensions
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X-Small: 9"
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Medium: 12"
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With few exceptions, online retailers of dog products will either not accept returns under any circumstance or their return policies are very limited. Here is the truth: Return policies for dog products are very restrictive industry-wide because once your dog has had contact, it cannot be resold. We guarantee that everything you buy from us will be in brand new condition when you receive it, and we want to keep it that way.
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SPRINGFIELD – The City Council, after hearing from members of the Fire Department and the public, will consider changing the qualifications for fire commissioner on Monday that, if approved, will allow Mayor Domenic J. Sarno to appoint his choice for the permanent job, Joseph A. Conant.
The meeting is at 7 p.m. at the council chambers at City Hall.
Under the ordinance, as recently proposed by Sarno, the fire commissioner must have at least 10 years of experience in fire service, including at least five years at the level of district chief or deputy chief, which Conant has achieved. In addition, the fire commissioner must have a bachelor's degree or be pursuing a bachelor's degree, under the new minimum qualifications.
The current ordinance, enacted in 2006, requires the fire commissioner to have a master's degree and at least seven years experience as a deputy chief or its equivalent. Conant, pursuing a bachelor's degree at the University of Massachusetts, does not meet the requirements of the 2006 ordnance.
Conant has served as acting fire commissioner since January of 2012, as appointed by Sarno, and the mayor said he will make the permanent promotion as soon as possible. Sarno said he fully supports Conant, and has no intention of conducting a nationwide search for candidates as suggested by some residents.
In December, firefighters presented a petition signed by 139 firefighters, supervisors and retirees, strongly supporting Conant for fire commissioner.
In other action, the council will consider approving a citywide ballot on casino gambling, rather than have the vote take place solely in the ward where two casinos are being proposed. A date for the ballot vote is not yet determined, but the council has the power to approve either a citywide vote or ward vote, under state law.
Springfield City Council considers passing new qualfications for fire commissioner
Peter Goonan | email@example.com By
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on January 11, 2013 at 6:53 PM, updated January 13, 2013 at 4:46 PM
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on January 11, 2013 at 6:53 PM, updated January 13, 2013 at 4:46 PM


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Only two more months till the NFL draft. Which means mock drafts. Lots and lots of mock drafts. It's all mock drafts these days.
Many draft analysts, including this dude, have taken a stab at who they think the Jets might take with the 18th pick. At least one has even thrown a dart at a trade, never mind that we haven't yet waded into free agency, which will likely have a profound impact on many teams' needs long before the draft takes place. But why worry about that stuff now?
Here, then, as of Thursday, March 6, 2014, is your post-combine Jets mock draft roundup. I googled them so you don't have to. You'll notice there's lots of Marqise Lee and Brandon Cooks, and everyone has the Jets taking either a receiver or a tight end.
Just a hunch, but there will probably be some changes made between now and the real thing:
Matt Smith, NFL.com: Odell Beckham Jr., WR, LSU
Bucky Brooks, NFL.com: Marqise Lee, WR, USC
Charles Davis, NFL.com: Eric Ebron, TE, North Carolina
Todd McShay, ESPN.com: Marqise Lee, WR, USC
Eddie Brown, U-T San Diego: Marqise Lee, WR, USC
Doug Farrar, SI.com: Marqise Lee, WR, USC
Shaun King, Yahoo: Marqise Lee, WR, USC
WalterFootball.com: Brandin Cooks, WR, USC
Pat Kirwan, CBSSports.com: Marqise Lee, WR, USC
Connor Rogers, Turn On The Jets: Brandin Cooks, WR, Oregon State
Alex Espinoza, Bleacher Report: Eric Ebron, TE, North Carolina
Pete Prisco, CBSSports.com: Marqise Lee, WR, USC
Daniel Jeremiah, NFL.com: Brandin Cooks, WR, Oregon State
Dane Brugler, CBSSports.com: Odell Beckham Jr., WR, LSU
Will Brinson, CBSSports.com: Kelvin Benjamin, WR, Florida State
Matthew Fairburn, SB Nation: Traded to Panthers for first-, third-, and fourth-round picks, because, sure, why not? Then has Jets taking Marqise Lee, WR, USC, at No. 28.
Rob Rang, CBSSports.com: Eric Ebron, TE, North Carolina
Draftek.com: Marqise Lee, WR, USC
A.J. Perez, NJ.com: Eric Ebron, TE, North Carolina


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Highmark Releases Latest Federal Enrollment Numbers And Sees Significant Interest In Its Community Blue Plans In Pennsylvania
December 10, 2013
PITTSBURGH — Highmark has seen incremental improvement in the number of enrollments received through the federal health insurance marketplace during the past month.
Highmark's current enrollment* through the federal marketplace to date is:
- Pennsylvania: 10,112
- West Virginia: 1,237
- Delaware: 651
Highmark is committed to making affordable health care coverage available to individuals and offers the lowest priced health plans on the marketplaces in Pennsylvania and Delaware, and in West Virginia, we are the only insurer on the marketplace.
There is a continual need to improve the functionality of the federal marketplace and encourage consumers to enroll by Dec. 23, 2013 for the earliest effective date of Jan. 1, 2014.
In the state of Pennsylvania, Highmark has seen significant interest in its Community Blue plans, which leverage a highly-efficient network of community hospitals and doctors to provide quality care at a lower price. Of all of the plans sold by Highmark on the federal marketplace, 76 percent of those in western Pennsylvania and 80 percent of those in central Pennsylvania have been Community Blue plans.
"We believe that select-network plans, like Community Blue, are one of the health insurance industry's best tools to help members lower their health care costs," said Deborah Rice-Johnson, president of Highmark's health plans.
*Enrollment numbers as of Dec. 9, 2013 are of those who have been loaded to Highmark's system through completed on-exchange enrollments (834s that have been verified and processed by Highmark). These enrolled members may have not yet paid their first month's premium, therefore have not completed the entire enrollment process.
About Highmark Inc.
Highmark Inc. is among the largest health insurers in the United States and the fourth-largest Blue Cross and Blue Shield-affiliated company. Highmark operates health insurance plans in Pennsylvania, Delaware and West Virginia that serve 5.3 million members. Its diversified health businesses serve group customer and individual health needs across the United States through dental insurance, vision care and other related health businesses. Highmark is an independent licensee of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield companies. For more information, visit www.highmark.com.
The Blue Cross and Blue Shield Association is a national federation of 36 independent, community-based and locally-operated Blue Cross and Blue Shield companies that collectively provide healthcare coverage for more than 106 million members members – one-in-three Americans. For more information on the Blue Cross and Blue Shield Association and its member companies, please visit bcbs.com. We encourage you to connect with us on Facebook, check out our videos on YouTube, follow us on Twitter and check out The BCBS Blog, for up-to-date information about BCBSA.


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Kara Giacobini is known to be associated with the Geno "John" Amato crime syndicate.
Kara Giacobini also is a member of the Damasso Galichio crime family and working in "Galichio" Crew.
Family Boss - Damasso Galichio
Underboss - William "Billy Boy" Galichio
Consigliere - Roberto "Small Print" Galichio
Capo - Adamo "Curly" Galichio
Enforcer - Bellino "Sparks" Perugini
Soldier - Davide "Trip" Galichio
Soldier - Nanda "Pie" Renaldini
Soldier - Elda "E-Trade" Tarquini
Soldier - Ottavio "Skin" Macrillo
Soldier - Fedele "Web" Bartolomeo
Soldier - Giorgio "Hollywood" Episcopo
Soldier - Enrico "The Nose" Eduardini
Weapons expert for the Galichio crew. He is expert in acquiring and distributing guns of all types. He is always dealing in disposable and untraceable handguns. It's been said that half the weight he carries around with him every day, is gun metal. KG also helps distribute weapons for the other crews in the family. Not all of them, but quite a few.
If you have any information concerning this person, please contact your local "G" MAN
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Current Time: 10/24/2016 08:56:26 Pacific Daylight Time (15:56 GMT)Last Updated: 2016-03-17T07:16:10Z on 03/17/2016 00:16:10 Pacific Daylight Time (07:16 GMT) Rendered From:UnknownCoordinates are in the WGS84 datum


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The Delaware River Joint Toll Bridge Commission unanimously approved a formal policy that requires the bi-state agency to conduct public hearings and gather public comment before enacting rate changes at the Commission's toll bridges.
Joseph J. Resta, who became the Commission's executive director in February, said the policy will ensure enhanced transparency and openness should the Commission ever need to adjust its toll rate schedule. He noted that the agency received some criticism at the time of its 2011 toll adjustment – which raised the base car toll by 25 cents to $1 – because it decided not to hold hearings on the increase, citing that the $1 rate had been subjected to public hearings in 2001.
Resta said the new policy is in line with the updating of policies and procedures that he called for in his monthly report to the Commission in April.
"While we are working to update policies and procedures such as records retention, open records, surplus property disposal, and contract compliance policy, could there be any area more important for examination and modification than the way the Commission goes about establishing the rate schedules at its toll bridges?" Resta asked. "Tolls are the fiduciary connection with the public that this Commission was created to serve."
The policy's provisions are as follows:
• For any proposed toll adjustment impacting any Commission-tolled facility, the Commission shall hold six public hearings – with two hearings (one in each of Pennsylvania and New Jersey) in each of the Commission's three districts, with appropriate Commissioner representation.
• The last public hearing shall be held at least 30 days prior to the date on which the Board of Commissioners shall consider a resolution approving such proposed toll adjustment.
• The Commission shall publish notice(s) of each public hearing at least 10 days prior to the hearing date. The notice(s) shall be published on the Commission's website. The "Preserving Our Past, Enhancing Our Future" notice(s) also shall be published in newspapers in New Jersey and Pennsylvania, in the same manner in which regular monthly Commission meetings are advertised.
• The proposed toll schedule shall be published on the Commission's website at least 10 days prior the first public hearing, and shall remain on the website until it is considered by the Board of Commissioners.
• Each public hearing shall provide the opportunity for the public to provide comment on the proposed toll adjustment.
• The Commission also shall accept public comment via email, web application or mail.
• Commission staff shall summarize, in writing, the public comment(s) received and circulate such written summary to the Board Members for consideration prior to the Board of Commissioners' consideration of a resolution approving the toll adjustment.
• The public also shall be afforded the opportunity to provide comment on the proposed toll adjustment during the meeting of the Board of Commissioners at which the resolution approving the toll adjustment will be considered, during the appointed time for public comment on agenda items.
Resta noted that today's action on the toll hearing policy should not be misconstrued as a preparatory step for a change in the Commission's toll rates.
"This policy should not be construed as a precursor to any kind of toll adjustment action by the Commission in the near future," said Resta. "There are no plans for a toll adjustment at this time."
Resta said the policy meshes with a series of changes he outlined for Commission operating systems and procedures back in April:
"The primary goal is to foster changes, provoke discussions and facilitate improvements that will enable the Commission to fulfill its ultimate objective – serving the public to the best of our ability," Resta said.


text: The Integrated Program in Cellular, Molecular and Biomedical Studies (CMBS) is an interdepartmental degree-granting program offering pre-doctoral training for students at the Columbia University Medical Center. The CMBS Program presents students with a unique opportunity to obtain rigorous training in an individualized environment. The CMBS Program is composed of faculty from each of the basic science departments at Columbia University Medical Center and the Center for Computational Biology and Bioinformatics.


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Looked like a fun comedy that might successfully blend a little action via car chases and shootouts that few modern comedies manage to deliver, in the vein of "Beverly Hills Cop," "The Blues Brothers" or "Midnight Run."
Coming up short in that arena was David Gordon Green and Judd Apatow's "Pineapple Express," the rare stoner action flick that came through on the jokes OK but fell short when bullets started flying.
This time, director Ruben Fleischer ("Zombieland") brings some action experience to the table, along with a particularly funny crop of talent in Jesse Eisenberg, Aziz Ansari, Danny McBride and Nick Swardson. So if the bank robberies and car chases don't get it done, those four will at least bring the laughs.
And that was that. Until recently, when I found out that the film's story about a pizza guy who is kidnapped and forced to rob a bank with a real bomb strapped to his chest was ripped from the headlines.
That's right, this is loosely based on the true story of American pizza delivery man Brian Wells, who was killed by a time bomb fastened to his neck by "friends," or would-be robbers. Shortly after police arrested Wells and called the bomb squad, the device exploded and killed the man, who police eventually determined was in on the robbery.
So does that change things? Am I uncomfortable now knowing the filmmakers are making light of such as bizarre and disturbingly true story that only happened eight years ago? Kind of.
As long as Ansari and McBride say enough funny stuff to help forget about the real thing during the hyper-brisk 80-minute running time, I suppose we can let it slide.
For those sitting this one out, here's what's happening:
Live music tonight: Catch Sean Rivers at the Dixie on the Strip, Andy Hall at Five Restaurant, Plato Jones at Gnemi's, Slang at Rhythm & Brew's, a dance party with Brian Oliu and a three-band lineup at Green Bar, including Conclave, Hail the Titans and Capgun Suicide.
"Nunsense" at the Bama Theatre: The musical comedy about tap-dancing nuns presented by Actor's Charitable Theatre will play tonight through Sunday at 7:30 p.m. There will also be matinees on Saturday and Sunday at 2 p.m. Tickets range from $18-20.
Wilhagan's 10th Anniversary Party on Sunday: The sports bar turns 10 on Sunday, so go celebrate the longevity of another quality Tuscaloosa establishment. The bar is serving a free dinner buffet and $1 beer starting at 5 p.m., so there's your excuse. There will be other drink specials and door prizes given away throughout the evening. Here's to another 10 years.


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Actress-Singer-Songwriter, Minnie Driver, has already proven to herself that at 37 she can do it all. Star in movies who will earn her Oscar Nominations alongside small independent projects that are close to her heart, sing in movies and write her own tunes and publish them successfully not to mention star in the critically acclaimed FX show, The Riches. Now it seems she is up for the biggest challenge of her life as she expects her first child... I got to sit down for a one-on-one with Driver for the release of her latest flick, Take.
|Minnie Driver


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Bravo for BitGravity! On Monday, the would-be Akamai (Nasdaq: AKAM ) killer announced an expansion of its existing partnership with Tata Communications (NYSE: TCL ) . Tata also pledged $11.5 million in additional funding for the upstart.
Is this how Akamai dies?
It's news like this that seems to be spooking Akamai investors. They're wondering whether this Rule Breakers recommendation is permanently broken. (Shares of Akamai are down more than 45% year to date.)
I don't think so. Here's why:
Over the last couple of years we saw a tremendous amount of growth related to broadband adoption. This year we've seen that moderate a little. I think we'll see a second wave as we go from [1 terabit per second] to 500 [terabits per second]. We think in order to scale, you can't do that from a centralized architecture, you have to do that from the edge where the capacity is the most abundant and the least expensive. I think what we'll see is it will be a little bit slower to come but bigger than most people expect.
Those are comments from Akamai Chief Financial Officer J.D. Sherman at a recent investor conference sponsored by Citi. Notice the language -- Sherman is conceding that Akamai's growth story faces shorter-term challenges.
What I find interesting, and comforting as an investor, is his take on competitive advantage. Translated, he's saying that Akamai is best positioned to handle the explosive growth of Web content.
A line in the Web
Is that really a fair claim? I can't be 100% sure. I've long been an Akamai bull because of its algorithm. But that's only one part of the story, according to company Senior Vice President of Networks and Operations Bobby Blumofe, whom I recently interviewed.
Think of a line, he says. On the left side of the line is the Internet, and on the right side are users. Akamai's servers operate on the right side. BitGravity, Internap (Nasdaq: INAP ) , Limelight Networks, and others operate on the left side. So long as the bridge -- the interconnection -- between the Web and users is reasonably fast, this isn't too large of a problem to overcome. Live video can be delivered straight to users a la BitGravity, for example.
The trouble is that the interconnection has limits. As Blumofe explains:
If the servers are on the wrong side of the link, then every viewer causes an additional copy to be streamed over that link. For example, consider a 1 [megabit-per-second] stream, maybe TV quality, with an ISP having 10,000 viewers. In that case, that ISP is going to have 10 [gigabits] of traffic going over their uplink. That's a lot of load, and they likely don't have that much spare capacity on that link.
Thus, according to Akamai, the line between the Web and ISPs such as AT&T (NYSE: T ) and Verizon (NYSE: VZ ) becomes a brick wall. Crossing at full speed is impossible, and what should have been a live feed dies.
Contrast that with how Akamai works. By modeling itself in the same decentralized style as the Internet itself, and by using an algorithm that allows data to be broken into bite-size chunks and then reassembled very close to its destination, Akamai doesn't need the delivery system -- the interconnect between users and the Internet -- to scale. Rather, Akamai's algorithm and architecture scale the Web.
Or at least that's the theory. It could take years for Akamai to be proved right, if ever. BitGravity points to Akamai's storage problem. And Google (Nasdaq: GOOG ) and Microsoft (Nasdaq: MSFT ) are among those spending billions to beef up the connections between the cloudy confines of the Web and the ISPs that deliver data.
But even here Blumofe is skeptical. He asserts that unless these connections become the digital equivalent of a 100-lane multi-terabit highway -- versus the five-lane gigabit highway we have today -- no CDN positioned on the wrong side of the line will scale to the degree that Akamai can. Patient investors will thus be rewarded.
I think he's right. I've bet my hard-earned dollars on it. Do you agree? Disagree? Use the comments box below to express your point of view.
Get your clicks with related Foolishness:
- There's more to Akamai than video.
- Here's how my tech portfolio will crush the market.
- Check out these three tech stocks.


text:
SPRINGFIELD – The sellout MassMutual Center crowd got exactly what it came to see.
In front of 7,331 fans packed to the rafters, the University of Massachusetts men's basketball team raced past high-powered Brigham Young 105-96 Saturday at the third annual Holiday Hall of Fame Showcase.
The win improved the Minutemen to 8-0, their best record since 1995-96.
UMass coach Derek Kellogg, who was stopped by countless supporters for handshakes and well wishes as he made his way to the postgame press conference, spoke highly of the dangerous opponent his team controlled for most of the game.
"(That is) a team I really respect in Brigham Young. I think they're a well-coached, very good team, and I thought our guys brought it today. It really could've went either way, but I thought our older guys played well. They came and brought it," he said. "And for me, it was great that we had a sold out MassMutual Center. It was kind of a special day for the program to be in Springfield and win a game against a pretty close to nationally ranked team."
Spurred by the raucous crowd and the type of nonstop, back-and-forth tempo he craves, senior point guard Chaz Williams paced the Minutemen with a pair of career highs: 32 points and 15 assists. He shot 9-for-14 overall, 5-for-7 from beyond the arc and 9-for-9 from the line, and scored 17 of his team's final 26 points.
» Click here to view more photos from the game
Williams, however, was more pleased with the work he did to set up his teammates.
"(That's) teammates making shots. You know, 15 assists, I credit those guys. They were open, and they always tell me 'If I'm open, I'm going to make it for you.' And that's what they did tonight," he said.
"Honestly, I'm not really a big point guy. I'm more impressed with the 15 assists than anything. Just getting my guys involved and having them feel comfortable with playing and just being on the floor with me is more exciting than scoring."
Kellogg was also pleased with the helping hand Williams displayed to give UMass a 29-15 assist advantage.
"I thought that was a really nice job of our guys sharing the basketball," he said. "We did a much better job against the zone and them kind of mixing up defenses than we have in years past. And the guys played selfless. They played to win, which is slowly becoming a staple of this team and what I'm most proud of."
Almost exactly half of Williams' statistics – 16 points and eight assists – came in the first half as the Minutemen fended off eight quick BYU (7-3) points and made an 11-0 run of their own en route to a 52-41 halftime lead.
With junior center and scoring leader Cady Lalanne sidelined for all but four of the first 20 minutes, UMass, as it has so often this season, relied on varied sources for
Senior forward Sampson Carter, coming off a string of low-scoring games, scored a season-high 20. Senior forward Raphiel Putney made three 3-pointers and added 15.
Junior forward Maxie Esho, an athletic force crucial in breaking the middle of BYU's 2-3 zone defense, scored 12 to go with six rebounds, two steals and two blocks.
"I thought his athleticism in the paint area got us going in the first half," Kellogg said of Esho. "And not only in the offensive end; he also came up with a couple defensive rebounds."
Esho thought the zone Eastern Michigan threw at UMass Tuesday helped him prepare for BYU. "I was just trying to stay aggressive and attack the middle of the zone," he said.
Esho scored six points in response to another Cougar run in the opening minutes out of the break as the Minutemen went on a 21-5 run.
Kellogg, who said he thought his team appeared to be going through the motions, called a quick timeout to calm his players and let them know BYU wasn't about to back down.
"This team's coming to play," he said. "I've watched them on tape enough (to know) that they can run off 25 points before you blink. The timeout wasn't anything totally Xs and Os; more 'Settle down, but also play harder.'"
"When they went on that run after (halftime)," Carter said, "the first thing I did was drop my head and say 'OK, they're here now. Try not to force anything and wake up.' After that, I just realized that, now that they're here, we have to finish everything around the rim. And that neutralized the game."
Junior guards Tyler Haws (25 points) and Matt Carlino (23 points, six assists) led BYU, while freshman big man Eric Mika, who struggled with early foul trouble, added 18 points and eight rebounds.
Sophomore guards Trey Davis (11) and Derrick Gordon (10) also reached double scoring figures for the Minutemen, who are off until Saturday when they host Northern Illinois at the Mullins Center.


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According to the updated ESPN rankings, the Michigan Wolverines have the 10th-best recruiting class in the country for the 2012-2013 season, which is excellent for a team that has struggled to attract top players ever since the Fab Five debacle.
This ranking can be attributed to three 4-star recruits in ESPN's top 100 who have signed letters of intent to play for Michigan: Mitch McGary, Glenn Robinson III and Nik Stauskas.
Here is an updated scouting report on these three players.