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Most Cited Pharmacology & Therapeutics Articles
The most cited articles published since 2011, extracted from Scopus.
Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variationUlrich M. Zanger | Matthias Schwab
Volume 138, Issue 1, April 2013, Pages 103-141
Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s. © 2013 Elsevier Inc.
Immune system to brain signaling: Neuropsychopharmacological implicationsLucile Capuron | Andrew H. Miller
Volume 130, Issue 2, May 2011, Pages 226-238
There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations. © 2011 Elsevier Inc.
Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive reviewPeter Csermely | Tamás Korcsmáros | Huba J M Kiss | Gábor London | Ruth Nussinov
Volume 138, Issue 3, June 2013, Pages 333-408
Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only give a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The "central hit strategy" selectively targets central nodes/edges of the flexible networks of infectious agents or cancer cells to kill them. The "network influence strategy" works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved by targeting the neighbors of central nodes/edges. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach. © 2013 Elsevier Inc.
GDNF, NGF and BDNF as therapeutic options for neurodegenerationShelley J. Allen | Judy J. Watson | Deborah K. Shoemark | Neil U. Barua | Nikunj K. Patel
Volume 138, Issue 2, May 2013, Pages 155-175
Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. GDNF administration has recently been shown to be an effective treatment for Parkinson's disease, with clinical trials currently in progress. Trials with NGF for Alzheimer's disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain-barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process. © 2013 Elsevier Inc.
Nicotinic acetylcholine receptors: From basic science to therapeuticsRaymond Hurst | Hans Rollema | Daniel Bertrand
Volume 137, Issue 1, January 2013, Pages 22-54
Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic. © 2012 Elsevier Inc.
The gut microbiome as therapeutic targetPatrice D. Cani | Nathalie M. Delzenne
Volume 130, Issue 2, May 2011, Pages 202-212
Obesity, type-2 diabetes and low-grade inflammation are becoming worldwide epidemics. In this regard, the literature provides a novel concept that we call "MicrObesity" (Microbes and Obesity), which is devoted to deciphering the specific role of dysbiosis and its impact on host metabolism and energy storage. In the present review, we discuss novel findings that may partly explain how the microbial community participates in the development of the fat mass development, insulin resistance and low-grade inflammation that characterise obesity. In recent years, numerous mechanisms have been proposed and several proteins identified. Amongst the key players involved in the control of fat mass development, Fasting induced adipose factor, AMP-activated protein kinase, G-protein coupled receptor 41 and G-protein coupled receptor 43 have been linked to gut microbiota. In addition, the discovery that low-grade inflammation might be directly linked to the gut microbiota through metabolic endotoxaemia (elevated plasma lipopolysaccharide levels) has led to the identification of novel mechanisms involved in the control of the gut barrier. Amongst these, the impacts of glucagon-like peptide-2, the endocannabinoid system and specific bacteria (e.g., Bifidobacterium spp.) have been investigated. Moreover, the advent of probiotic and prebiotic treatments appears to be a promising "pharmaco-nutritional" approach to reversing the host metabolic alterations linked to the dysbiosis observed in obesity. Although novel powerful molecular system biology approaches have offered great insight into this "small world within", more studies are needed to unravel how specific changes in the gut microbial community might affect or counteract the development of obesity and related disorders. © 2011 Elsevier Inc.
Stress management at the ER: Regulators of ER stress-induced apoptosisAdrienne M. Gorman | Sandra J M Healy | Richard Jäger | Afshin Samali
Volume 134, Issue 3, June 2012, Pages 306-316
The endoplasmic reticulum (ER) is an elaborate cellular organelle essential for cell function and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins which are detected by ER transmembrane receptors that initiate the unfolded protein response (UPR) to restore normal ER function. If the ER stress is prolonged, or the adaptive response fails, apoptotic cell death ensues. Many studies have focused on how this failure initiates apoptosis, particularly because ER stress-induced apoptosis is implicated in the pathophysiology of several neurodegenerative and cardiovascular diseases. In this review we aim to shed light on the proteins that are not core components of the UPR signaling pathway but which can influence the course of the ER stress response by regulating the switch from the adaptive phase to apoptosis. © 2012 Elsevier Inc. All rights reserved.
Structure, function and pathophysiology of protease activated receptorsMark N. Adams | Rithwik Ramachandran | Mei Kwan Yau | Jacky Y. Suen | David P. Fairlie | Morley D. Hollenberg | John D. Hooper
Volume 130, Issue 3, June 2011, Pages 248-282
Discovered in the 1990s, protease activated receptors 1 (PARs) are membrane-spanning cell surface proteins that belong to the G protein coupled receptor (GPCR) family. A defining feature of these receptors is their irreversible activation by proteases; mainly serine. Proteolytic agonists remove the PAR extracellular amino terminal pro-domain to expose a new amino terminus, or tethered ligand, that binds intramolecularly to induce intracellular signal transduction via a number of molecular pathways that regulate a variety of cellular responses. By these mechanisms PARs function as cell surface sensors of extracellular and cell surface associated proteases, contributing extensively to regulation of homeostasis, as well as to dysfunctional responses required for progression of a number of diseases. This review examines common and distinguishing structural features of PARs, mechanisms of receptor activation, trafficking and signal termination, and discusses the physiological and pathological roles of these receptors and emerging approaches for modulating PAR-mediated signaling in disease. © 2011 Elsevier Inc.
Therapeutic applications of compounds in the Magnolia familyYoung Jung Lee | Yoot Mo Lee | Chong Kil Lee | Jae Kyung Jung | Sang Bae Han | Jin Tae Hong
Volume 130, Issue 2, May 2011, Pages 157-176
The bark and/or seed cones of the Magnolia tree have been used in traditional herbal medicines in Korea, China and Japan. Bioactive ingredients such as magnolol, honokiol, 4-O-methylhonokiol and obovatol have received great attention, judging by the large number of investigators who have studied their pharmacological effects for the treatment of various diseases. Recently, many investigators reported the anti-cancer, anti-stress, anti-anxiety, anti-depressant, anti-oxidant, anti-inflammatory and hepatoprotective effects as well as toxicities and pharmacokinetics data, however, the mechanisms underlying these pharmacological activities are not clear. The aim of this study was to review a variety of experimental and clinical reports and, describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of Magnolia and/or its constituents. © 2011 Elsevier Inc.
G protein-coupled receptor kinases: More than just kinases and not only for GPCRsEugenia V. Gurevich | John J G Tesmer | Arcady Mushegian | Vsevolod V. Gurevich
Volume 133, Issue 1, January 2012, Pages 40-69
G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation- independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson's disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson's disease. © 2011 Elsevier Inc. All rights reserved.
Excessive discounting of delayed reinforcers as a trans-disease process contributing to addiction and other disease-related vulnerabilities: Emerging evidenceWarren K. Bickel | David P. Jarmolowicz | E. Terry Mueller | Mikhail N. Koffarnus | Kirstin M. Gatchalian
Volume 134, Issue 3, June 2012, Pages 287-297
Delay discounting describes the devaluation of a reinforcer as a function of the delay until its receipt. Although all people discount delayed reinforcers, one consistent finding is that substance-dependent individuals tend to discount delayed reinforcers more rapidly than do healthy controls. Moreover, these higher-than-normal discounting rates have been observed in individuals with other behavioral maladies such as pathological gambling, poor health behavior, and overeating. This suggests that high rates of delay discounting may be a trans-disease process (i.e., a process that occurs across a range of disorders, making findings from one disorder relevant to other disorders). In this paper, we argue that delay discounting is a trans-disease process, undergirded by an imbalance between two competing neurobehavioral decision systems. Implications for our understanding of, and treatment for, this trans-disease process are discussed. © 2012 Elsevier Inc. All rights reserved.
Insulin in the brain: There and back againWilliam A. Banks | Joshua B. Owen | Michelle A. Erickson
Volume 136, Issue 1, October 2012, Pages 82-93
Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathwayJiri Polivka | Filip Janku
Volume 142, Issue 2, January 2014, Pages 164-175
Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine. © 2013 Elsevier Inc.
A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicityAnna Astashkina | Brenda Mann | David W. Grainger
Volume 134, Issue 1, April 2012, Pages 82-106
Drug candidate and toxicity screening processes currently rely on results from early-stage in vitro cell-based assays expected to faithfully represent essential aspects of in vivo pharmacology and toxicology. Several in vitro designs are optimized for high throughput to benefit screening efficiencies, allowing the entire libraries of potential pharmacologically relevant or possible toxin molecules to be screened for different types of cell signals relevant to tissue damage or to therapeutic goals. Creative approaches to multiplexed cell-based assay designs that select specific cell types, signaling pathways and reporters are routine. However, substantial percentages of new chemical and biological entities (NCEs/NBEs) that fail late-stage human drug testing, or receive regulatory "black box" warnings, or that are removed from the market for safety reasons after regulatory approvals all provide strong evidence that in vitro cell-based assays and subsequent preclinical in vivo studies do not yet provide sufficient pharmacological and toxicity data or reliable predictive capacity for understanding drug candidate performance in vivo. Without a reliable translational assay tool kit for pharmacology and toxicology, the drug development process is costly and inefficient in taking initial in vitro cell-based screens to in vivo testing and subsequent clinical approvals. Commonly employed methods of in vitro testing, including dissociated, organotypic, organ/explant, and 3-D cultures, are reviewed here with specific focus on retaining cell and molecular interactions and physiological parameters that determine cell phenotypes and their corresponding responses to bioactive agents. Distinct advantages and performance challenges for these models pertinent to cell-based assay and their predictive capabilities required for accurate correlations to in vivo mechanisms of drug toxicity are compared. © 2011 Elsevier Inc.
Drug transport by Organic Anion Transporters (OATs)Gerhard Burckhardt
Volume 136, Issue 1, October 2012, Pages 106-130
Common to all so far functionally characterized Organic Anion Transporters (OATs) is their broad substrate specificity and their ability to exchange extracellular against intracellular organic anions. Many OATs occur in renal proximal tubules, the site of active drug secretion. Exceptions are murine Oat6 (nasal epithelium), human OAT7 (liver), and rat Oat8 (renal collecting ducts). In human kidneys, OAT1, OAT2, and OAT3 are localized in the basolateral membrane, and OAT4, OAT10, and URAT1 in the apical cell membrane of proximal tubule cells, respectively. In rats and mice, Oat1 and Oat3 are located basolaterally, and Oat2, Oat5, Oat9, Oat10, and Urat1 apically. Several classes of drugs interact with human OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, β-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs. For most drugs, interaction was demonstrated in vitro by inhibition of OAT-mediated transport of model substrates; for some drugs, transport by OATs was directly proven. Based on IC50 values reported in the literature, OAT1 and OAT3 show comparable affinities for diuretics, cephalosporins, and nonsteroidal anti-inflammatory drugs whereas OAT2 has a lower affinity to most of these compounds. Drug-drug interactions at OAT1 and OAT3 may retard renal drug secretion and cause untoward effects. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, and OAT10 to nicotinate absorption. OAT4 is in addition able to release drugs, e.g. diuretics, into the tubule lumen. © 2012 Elsevier Inc.
SDF-1α as a therapeutic stem cell homing factor in myocardial infarctionSanthosh K. Ghadge | Silke Mühlstedt | Cemil Özcelik | Michael Bader
Volume 129, Issue 1, January 2011, Pages 97-108
Myocardial infarction is associated with persistent muscle damage, scar formation and depressed cardiac performance. Recent studies have demonstrated the clinical significance of stem cell-based therapies after myocardial infarction with the aim to improve cardiac remodeling and function by inducing the reconstitution of functional myocardium and formation of new blood vessels. Stem cell homing signals play an important role in stem cell mobilization from the bone marrow to the ischemic cardiac environment and are therefore crucial for myocardial repair. To date, the most prominent stem cell homing factor is the chemokine SDF-1α/CXCL12. This protein was shown to be significantly upregulated in many experimental models of myocardial infarction and in patients suffering from ischemic cardiac diseases, suggesting the involvement in the pathophysiology of these disorders. A number of studies focused on manipulating SDF-1α and its receptor CXCR4 as central regulators of the stem cell mobilization process. Targeted expression of SDF-1α after myocardial infarction was shown to result in increased engraftment of bone marrow-derived stem cells into infarcted myocardium. This was accompanied by beneficial effects on cardiomyocyte survival, neovascularization and cardiac function. Thus, the SDF-1/CXCR4 axis seems to be a promising novel therapeutic approach to improve post-infarction therapy by attracting circulating stem cells to remain, survive and possibly differentiate in the infarct area. This review will summarize clinical trials of stem cell therapy in patients with myocardial infarction. We further discuss the basic findings about SDF-1α in stem cell recruitment and its therapeutic implications in experimental myocardial infarction. © 2010 Elsevier Inc. All rights reserved.
Serotonin 5-HTMarcello Leopoldo | Enza Lacivita | Francesco Berardi | Roberto Perrone | Peter B. Hedlund
7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders
Volume 129, Issue 2, February 2011, Pages 120-148
Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT 7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. © 2010 Elsevier Inc. All rights reserved.
Targeting Notch signaling pathway in cancer: Clinical development advances and challengesNaoko Takebe | Dat Nguyen | Sherry X. Yang
Volume 141, Issue 2, February 2014, Pages 140-149
Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs. © 2013 Elsevier Inc. All rights reserved.
Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitorsHaythum O. Tayeb | Hyun Duk Yang | Bruce H. Price | Frank I. Tarazi
Volume 134, Issue 1, April 2012, Pages 8-25
Alzheimer's disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (Aβ) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials. © 2012 Elsevier Inc.
Targeting autophagy during cancer therapy to improve clinical outcomesJean M Mulcahy Levy | Andrew Thorburn
Volume 131, Issue 1, July 2011, Pages 130-141
Autophagy is a catabolic process that turns over long-lived proteins and organelles and contributes to cell and organism survival in times of stress. Current cancer therapies including chemotherapy and radiation are known to induce autophagy within tumor cells. This is therefore an attractive process to target during cancer therapy as there are safe, clinically available drugs known to both inhibit and stimulate autophagy. However, there are conflicting positive and negative effects of autophagy and no current consensus on how to manipulate autophagy to improve clinical outcomes. Careful and rigorous evaluation of autophagy with a focus on how to translate laboratory findings into relevant clinical therapies remains an important aspect of improving clinical outcomes in patients with malignant disease. © 2011 Elsevier Inc.
New targets and approaches in osteosarcomaJonathan Gill | Manpreet K. Ahluwalia | David Geller | Richard Gorlick
Volume 137, Issue 1, January 2013, Pages 89-99
Osteosarcoma is the most common primary tumor of bone. Approximately 2/3 of patients who present with localized osteosarcoma can be expected to be cured of their disease with surgery and routine chemotherapy. Only 1/3 of patients with metastases detectable at presentation will be cured. These survival trends have stagnated over the past 20 years using conventional chemotherapy. New agents need to be rationally investigated to strive for improvement in the survival of patients diagnosed with osteosarcoma. This manuscript will review the rationale for conventional chemotherapy used in the treatment of osteosarcoma, as well as agents in varying stages of development that may have promise for treatment in the future. © 2012 Elsevier Inc.
Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapseGeorge R. Breese | Rajita Sinha | Markus Heilig
Volume 129, Issue 2, February 2011, Pages 149-171
Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis-like process occurs during the course of repeated chronic alcohol exposures that is critical for the negative symptoms observed during alcohol withdrawal. Basic studies have provided evidence for specific neurotransmitters within identified brain sites being responsible for the negative emotion induced by the persistent cumulative adaptation following intermittent-alcohol exposures. After an extended period of abstinence, the cumulative alcohol adaptation increases susceptibility to stress- and alcohol cue-induced negative symptoms and alcohol seeking, both of which can facilitate excessive ingestion of alcohol. In the alcoholic, stressful imagery and alcohol cues alter physiological responses, enhance negative emotion, and induce craving. Brain fMRI imaging following stress and alcohol cues has documented neural changes in specific brain regions of alcoholics not observed in social drinkers. Such altered activity in brain of abstinent alcoholics to stress and alcohol cues is consistent with a continuing ethanol adaptation being responsible. Therapies in alcoholics found to block responses to stress and alcohol cues would presumably be potential treatments by which susceptibility for continued alcohol abuse can be reduced. By continuing to define the neurobiological basis of the sustained alcohol adaptation critical for the increased susceptibility of alcoholics to stress and alcohol cues that facilitate craving, a new era is expected to evolve in which the high rate of relapse in alcoholism is minimized. © 2010 Elsevier Inc. All rights reserved.
The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusionKoen Raedschelders | David M. Ansley | David D Y Chen
Volume 133, Issue 2, February 2012, Pages 230-255
Myocardial ischemia-reperfusion injury is an important cause of impaired heart function in the early postoperative period subsequent to cardiac surgery. Reactive oxygen species (ROS) generation increases during both ischemia and reperfusion and it plays a central role in the pathophysiology of intraoperative myocardial injury. Unfortunately, the cellular source of these ROS during ischemia and reperfusion is often poorly defined. Similarly, individual ROS members tend to be grouped together as free radicals with a uniform reactivity towards biomolecules and with deleterious effects collectively ascribed under the vague umbrella of oxidative stress. This review aims to clarify the identity, origin, and progression of ROS during myocardial ischemia and reperfusion. Additionally, this review aims to describe the biochemical reactions and cellular processes that are initiated by specific ROS that work in concert to ultimately yield the clinical manifestations of myocardial ischemia-reperfusion. Lastly, this review provides an overview of several key cardioprotective strategies that target myocardial ischemia-reperfusion injury from the perspective of ROS generation. This overview is illustrated with example clinical studies that have attempted to translate these strategies to reduce the severity of ischemia-reperfusion injury during coronary artery bypass grafting surgery. © 2011 Elsevier Inc. © 2011 Elsevier Inc. All rights reserved.
Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatmentChristopher Pittenger | Michael H. Bloch | Kyle Williams
Volume 132, Issue 3, December 2011, Pages 314-332
Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. © 2011 Elsevier Inc. All rights reserved.
Targeting interleukin-6 in inflammatory autoimmune diseases and cancersXin Yao | Jiaqi Huang | Haihong Zhong | Nan Shen | Raffaella Faggioni | Michael Fung | Yihong Yao
Volume 141, Issue 2, February 2014, Pages 125-129
Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. © 2013 Elsevier Inc. All rights reserved.


text:
we really enjoyed it, unfortunately only one night...
This is a very beautiful hotel in the countryside of Interlaken, you can breeze the fresh air from lake Brienz. Three star hotel with good and clean facilities.
The network connection is not that good, there's no use-able wireless, and only one wire connection in the conference room. People have to struggle for that resource...
Lucation, lake view
A lovely modern clean hotel right by the lake side and ferry. The room was clean if a little basic, but had a balcony and a superb lake view. The food was excellent. A lovely quiet location. Recommended.
How nice everyone was, The breakfast was good on the days we got to eat. The rooms were beautiful.
We were treated like gold the first day. Giving candy on are pillows. But after that we had to ask for anything. Just thought that was odd.
We really liked the peaceful environment at Hotel Bellevue in Iseltwald. After spending time in the city this was a peaceful retreat. Our room overlooked the lake and it was very serene. The room was very comfortable, staff were friendly and helpful and the breakfast was wonderful.
Here's why:
We're not the seller.
At KAYAK we don't set the prices, so it's not possible for us to guarantee what other companies are selling.
We compile tonnes of data for you
Our service lets you quickly and easily compare results from hundreds of travel sites at once. In this sense, KAYAK is a search engine and we can't guarantee prices we find.
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subset: commoncrawl


text:
Hi dribbblers, take a look at @2X version.
This shot is primary for fun and training - but I want to congratulate Squarespace to their big milestone and enjoy the celebrates. And here is little sweet present from me.
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(based on 2 reviews)
Reviewed by 2 customers
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Brooding, industrial and heartfelt
By Sazzy
from UK
Purchase Reason
Great use of light and shade, the detail in the churchyard and gates in the dark I really like and adds a different dimension again to the whole picture. The Pop of bright red is remarkable and a great stark contrast - I love this genre of Mackenzie Thorpe work.
Bottom Line Yes, I would recommend this to a friend
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By Juju
from Melbourne
Beautiful print
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Canon EOS 70D: Hands-on with a mid-range DSLR with a difference
The Canon EOS 70D is the latest mid-range model from the Japanese imaging company, replacing the EOS 60D. It comes four long years after the 60D, during which a huge amount has changed in the world of cameras. As such, the EOS 70D isn't just a spec refresh,... >>
Canon EOS 70D videos show off Dual Pixel CMOS AF prowess
Much of the new Canon EOS 70D might fit right into the line-up existing EOS DSLR cameras from the company, but it's the Dual Pixel CMOS AF technology that should attract your attention. The new autofocus technology is designed to address the woes when... >>
Canon EOS 70D official, 20.2-megapixel snapper with faster autofocus
Canon has announced the Canon EOS 70D with a new Dual Pixel CMOS focus that claims to autofocus five times faster than the previous EOS cameras in live view. Following on from the current EOS 60D, the new model will feature a 20.2-megapixel APS-C sensor... >>


text:
Queso Cheese Sauce
Total Time
Prep 0 mins
Cook 5 mins
This queso isn't so much a dip as it is a sauce. I use this to top my burritos, empanadas "Empanadas Con Queso" and enchiladas. I also pour this cheese sauce all over my rice and beans, too!! Enjoy!
Ingredients Nutrition
- 1 tablespoon unsalted butter
- 1 tablespoon flour
- 1 cup milk
- 1 cup monterey jack cheese, shredded
- 1⁄2 teaspoon cumin
- salt and pepper
- Melt butter in a small saucepan over medium heat.
- Whisk in flour and cook for about 1 minute.
- Whisk in milk gradually until incorporated.
- Gradually stir in cheese until melted.
- Season with cumin, salt and pepper to taste.
Most Helpful
Awesome sauce! I can't believe how so few ingredients make such a tasty sauce! DEELISH!!!
Wonderful sauce! :) We put it on our empanadas made with Empanada Dough. Dh grabbed pepper jack, but it went over well! :) Thanks, KPD!!


text:
San Diego Toreros at Stephen F. Austin Lumberjacks Basketball
Sat, Dec 1, 2012 6:00 pm
William R Johnson Coliseum, Nacogdoches, TX
Sorry, this event has already taken place. Please see similar events below.
|Nov 11 Fri 1:00 PM
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|Dec 22 Thu 3:30 PM
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|Reynolds Center
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text:
Only twenty more days until the Wii is released and I can't hardly wait. I know some people are thinking they would rather have a PS3. I am happy for those people that are going to pay 499 or 599 on the launch day. Besides I'll get a PS3 by my birthday without a doubt. Anyway back to the Wii subject, I think I may have got one of the last reserves in town yesterday. I called every store here even the shitty game store I don't like (not mentioning names). So I found one store with one reserve left (so they said)!!! I am glad I did I almost started crying when I couldn't find one. So twenty days and I will be playing some Wii sports / Twilight Princess!!!
Travitz West
- Total Points:
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- Rank:
- Hardcore
- Last Visit:
- 08/27/2013
- Currently:
- Offline
- Sex:
- Location:
- Springfield, MO
- XBox Live: travitz
- AIM Name: travitz13
My Favorites
Favorite Music:
Mindless Self Indulgence,
.... Everything,
(not country)
Favorite Books:
Ender's Game series,
MYST series,
Flowers for Algernon,
BONE comics,
A Clockwork Orange,
Eragon & Eldest
Favorite TV Shows:
Aqua Teen Hunger Force,
Invader Zim,
The Venture Brothers,
Arrested Development,
Tom goes to the Mayor,
Dead Like Me
Favorite Movies:
Clockwork Orange,
Star Wars,
Indiana Jones,
Resident Evil (trilogy),
Sin City,
Punch-Drunk Love
Favorite TV Shows:
Aqua Teen Hunger Force,
Invader Zim,
The Venture Brothers,
Arrested Development,
Tom goes to the Mayor,
Dead Like Me
Favorite Movies:
Clockwork Orange,
Star Wars,
Indiana Jones,
Resident Evil (trilogy),
Sin City,
Punch-Drunk Love
My Interests
Interests:Video Games, Writting Comics, Collecting Vintage Systems
Where I work:I currently work for RPCS (Ramey Price Cutter Super Markets) as a System Support Technician. Working on computers and registers in th IT dept.
What I like to do:Play video games, mostly rpg, or action/rpg
My Clubs
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We're giving away 5 SanDisk(R) Memory Stick PRO Duo(TM) gaming...
Oct 31, 2006 7:10AM PST
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text:
Introducing the Chris Craft Launch 36.
A day boat designed for families to have fun on the water.
We're your Exclusive West Coast Dealer of Chris Craft boats...
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text:
Catch up on shows currently on SundanceTV. Watch recent episodes on sundance.tv
Sundance Film Festival
HQ host, Aamer Haleem, interviews director Constance Marks and Kevin Clash of BEING ELMO: A PUPPETEER'S JOURNEY.
Sundance NEXT FEST 2016 Lights Up Downtown LA This Summer
5 Questions with Sundance 2016′s Next Generation Filmmakers
Sundance Film Festival 2016: 3 "Meet the Filmmaker" Videos


text:
ARM CEO Warren East steps down
Warren East, CEO of semiconductor firm ARM, is retiring from the company after almost 12 years in the leadership role
Warren East, CEO of semiconductor firm ARM, is retiring after almost 12 years in the leadership role.
Warren East – who was the winner of Computer Weekly's UKtech50 in 2012 – started at ARM in 1994, when he was brought in to form a new consultancy business for the Cambridge-based company.
Your exclusive guide to CIO trends
A collection of our most popular articles for IT leaders from the first few months of 2016, including: - Corporate giants recruit digitally-minded outsiders to drive transformation - Analytics platforms to drive strategy in 2016 - Next generation: The changing role of IT leaders.
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East rose to CEO in October 2001 and led ARM through a long period of growth, as it became the dominant force in the smartphone chip market – holding 95% market share in 2012 – and recording record profits in its last financial quarter.
However, East has decided his time is up and will retire at the end of June 2013, with no clues to what he will do next.
"It has been a privilege to lead ARM during such a momentous and exciting time for our industry and I am proud of what the ARM team of employees and partners has achieved together while I have been CEO," East said.
"ARM is a great company with a strong market position and a unique culture. We take a very long-term view about our business and we believe that now is the right time to bring in new leadership, to execute on the next phase of growth and plan even further into the future. "
East will be succeeded by Simon Segars, president of operations at ARM.
Simon Segars joined the company in 1991 and has held a number of senior roles in the UK and abroad. He will begin in the top job on 1 July 2013.
"I am honoured to have been appointed to succeed Warren, who has achieved so much in his time leading the business," said Segars. "Above all, Warren's vision of the ARM business model and commitment to the ARM partnership has been inspirational and has created a tremendous platform for future growth.
"I am keen to lead the company into the next phase of growth, working even more closely with [ARM chairman] John Buchanan, the board, our employees and our customers as well as continuing to develop the ARM partnership."
East gave his backing to the new CEO, adding: "I have worked with Simon in the senior leadership team for many years and we share a global perspective and belief in the ARM approach to partnership and collaboration.
"He is an excellent choice to lead ARM."
Enjoy the benefits of CW+ membership, learn more and join.


text:
damaged goods
Simple Definition of damaged goods
: products that are broken, cracked, scratched, etc.
: a person who is considered to be no longer desirable or valuable because of something that has happened : a person whose reputation is damaged
Full Definition of damaged goods
: a person considered to be flawed or spoiled in character, efficiency, or worth
First Known Use of damaged goods
Seen and Heard
What made you want to look up damaged goods? Please tell us where you read or heard it (including the quote, if possible).


text:
country song writer - download fast id:4IHj
country song writer.zip - download 2015
Name: country song writer.zip
Release: 2015
Type: WinZip
Total Downloads: 14196
License model: Shareware
Language: English
Last updated on: 01/18/2015 16:39:51
Supported OS: Windows 8, Windows 7, Windows Vista, Windows XP
Keys:01/18/2015 16:39:51
2/12/2007 · A Country Boy Can Survive - YouTube ... YouTube homeCountry music and entertainment magazine. Current news and profiles of country music's biggest names.Lyrics On Demand - Song Lyrics, Lyrics of Songs, Free Lyrics, Free Song Lyrics, Rap Lyrics, Country Lyrics, Hip Hop Lyrics, Rock Lyrics, Country Music Lyrics, Music ...Visit CMT.com for all that is Country Music; Artists, Photos, Videos, Shows, Online Radio and More. Get the latest Country Music News and Videos on your favorite Artists.Read the latest country music news from your favorite country music stars.This week's most popular country songs, based on radio airplay audience impressions as measured by Nielsen Music, sales data as compiled by Nielsen Music and ...Singer-songwriters are musicians who write, compose and perform their own musical material including lyrics and melodies. As opposed to contemporary pop music …The top source for the latest country music news, videos, songs, interviews and live performances from country's biggest stars.The mission of the Country Music Hall of Fame® and Museum is to identify and preserve the evolving history and traditions of country music and to educate its …"Imagine" is a song written and performed by the English musician John Lennon. The best-selling single of his solo career, its lyrics encourage the listener to ...
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Welcome, skip to the content.
Wine show at Federation Square, Melbourne
If you were given the task of describing the taste of Victoria, you'd be best to start your research at one of the state's many and varied food and wine events. Toast the vintages at parties in Victoria's distinct wine regions and get tips on matching wines to the state's fresh produce from superstar chefs cooking at award-winning regional restaurants. Victoria's fresh produce arguably tastes better when eaten outside and accompanied by live music and good friends – picking your own food or learning how to cook it are definitely bonuses.
Charge your glasses and Toast to the Coast; cool climate wines from The Bellarine and the Surf Coast, across to the Moorabool Valley and surrounds.
Peninsula Piers and Pinots is held on the Sunday of the Victorian Labor Day long weekend on the Flinders foreshore. Twenty Mornington Peninsula...
Raise a toast to regional producers and savour a meal and a glass of wine at delicious food festival events, including the World's Longest Lunch.
Victoria's original wine festival, the Rutherglen will once again be the place to be on the June long weekend for the annual Rutherglen Winery...
Cruise on down the Mornington Peninsula over the Queens Birthday break to sample local wines and share in the festivities of the Winter Wine Weekend.
We couldn't find any results that matched your search criteria.
Try changing your filters or search terms to try again.
Until 23 Oct 2016
25 Nov 2016
23 Oct 2016
Come and join Cuckoo Restaurant for a weekend of leather pants, beer games, playing with pretzels, yelling a yodel and slip slop slap dancing....
The Cake Bake & Sweets Show is the greatest baking, dessert and entertaining show on earth. Filled with everything from cakes, pastries and...
Back by popular demand, Hallowine will once more be held in the cellars of Mitchelton Winery. The theme Dreamscapes will conjure up a surrealist...
Launched in London in 2012, this is the inaugural year in Melbourne, brought together by two established voices, The Gin Queen and Gin Foundry. This...
Eating at a Fairweather Farmgate Facile Dinner is a relaxing experience, with a focus on enjoying great company and winding down for the weekend. The...
Enjoy a day in the country. The historic National Trust listed Mount Mitchell property will be hosting a springtime party this October. The...
The Food Trucks are in Prahran every Sunday at the Mt Erica! Come and join us for "Off The Beaten Truck", a mini-festival featuring incredible local...
One Sunday each month and fortnightly during winter Melbourne Zoo are serving a delicious High Tea in the Rainforest Room. Wander the beautiful...
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Enjoy the classic tradition of High Tea at Woodman Estate on Sundays. Arrive to white linen table cloths and napery. Savour the selection of estate...
Woodman Estate Hot Springs and High Tea. Treat yourself and loved one to this special event. Enjoy a day of indulgence and relaxation at two of the...
Yarra Ranges Estate proudly host seasonal Sunday lunches throughout the calendar year with a variety of live entertainment. Their platter and menu...
Under the same roof as Prahran Market you'll find a fabulous pantry overflowing with specialty food, cookware, recipe books and a cooking school.
Experience true Pizzini style in a warm family atmosphere while tasting top regional Italian varietals. Stay on at the Pizzini Vineyard guesthouse.
Katrina Pizzini's A tavola! Cooking School is based at Pizzini Wines in the King Valley. Katrina's hands on classes are held in a purpose built...
Deliberate over the all-day tapas and wine menu, visit the farm shop and join a Mornington Peninsula cooking class at this haven for food lovers.
Taste Yarra Glen's long history of gourmet indulgence at farmers markets and cellar doors.
Discover Beechworth's gold rush and bushranger history then explore the burgeoning restaurant scene.
Live the good life in Milawa and King Valley, one of Australia's oldest gourmet regions.
Perch yourself high above Melbourne and surrounds and observe the striking seasons of Olinda.
Get your foodie fix, visit cellar doors or experiencing extraordinary wildlife at Healesville.
Lead a double life in Daylesford, a village dedicated to wellbeing, a stone's throw from Melbourne.
Uncover history in every corner of this charming fishing village at the end of the Great Ocean Road.
Be charmed by the historic seaside village of Queenscliff with its elegant Victorian-era buildings.
Discover the taste of history with a fresh palate in Rutherglen, a historic wine growing area.
See Bright in its autumnal splendour, and visit the nearby snowfields and national parks.
Your Macedon Ranges food and wine journey isn't complete without a visit to the village of Kyneton.
Stroll by gold rush architecture and see why the village has been classified by the National Trust.
Travel from mountains to coast to city in no time at all thanks to Victoria's compact size. Follow tourist routes or make it up as you go along.
If Victorians know one thing, it's how to have fun. Feast on a smorgasbord of live music, comedy, arthouse cinema and local and international sport.
If it's relaxation you need, Victoria is the place for an indulgent escape, with its long spa tradition and over 100 springs throughout the state.
Find your flavour in Victoria, where cups runneth over with fine restaurants, eclectic cuisines, country pubs, regional produce and wineries galore.


text:
Sew Connected 2 so far
Dear Sew Connected 2 members: I am lame and have lost track of whose block is whose. I know some but there's a couple that are mysteries as I threw out packaging without making a note of it. Could you do me a favor and tag your block so that I know who I still need blocks from? Thank you for putting up with my lack of organization. Ha.
519 views
4 faves
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Taken on February 23, 2004


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realmagick.com The shrine of knowledge.
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No trip to the Sunshine Coast is complete without visiting SEA LIFE Mooloolaba!
Situated at Mooloolaba Wharf, just moments from the main Esplanade, SEA LIFE Mooloolaba is home to thousands of animals, including sharks, seals, turtles, stingrays, otters, sawfish, tropical fish and much, much more.
As one of the Sunshine Coast's leading family and tourist attractions, SEA LIFE Mooloolaba offers entertainment for young and old alike. Walk underwater through the glass viewing tunnel and see Australia's marine life like never before! Come within inches of huge sharks, rays and turtles and see some of the remarkable marine and freshwater animals that Australia is famous for.
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Book your tickets in advance here on the official SEA LIFE website and save up to 20%, compared to standard 'on the day' prices - but only when you book online!
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Whether you're a local looking for family activities in the Sunshine Coast region, or if you're just visiting the area on holiday, SEA LIFE Mooloolaba is a must-see visitor attraction.
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HourlyHours to be determined
Start DateFebruary 11, 2013
I need a qualified person to scrape several websites to find me leads. You should have a license for the high-end scraping software and be able to send me a CSV of the data.
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3) Any other info I need to know to prove to me that you're the best.
If you write anything other that the 3 paragraphs I will assume you don't follow instructions.
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About the Client
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3,543 Hours


text:
Al Jazeera English Stays On in Burlington, Vt.Municipal cable company Burlington Telecom reaches agreement to continue carrying network after controversy. 7/23/2008 04:32:00 AM Eastern
Al Jazeera English -- the English language spinoff of the controversial international Middle Eastern news network -- will stay on in Burlington, Vt.
Municipal cable company Burlington Telecom reached a contractual agreement with the network to continue carrying Al Jazeera English.
The channel has been available on BT since January 2007. But controversy erupted earlier this summer when BT general manager Chris Burns announced that he was dropping the channel due to what he characterized as persistent viewer complaints. However, a series of public forums to discuss the matter produced a lopsided majority in favor of keeping the channel.
Burlington; Toledo, Ohio; and Washington, D.C., are the only markets where Al Jazeera English is available.
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During an October 4th surprise performance at Nashville's historic Ryman Auditorium that sent social media into a frenzy, Tim McGraw and Faith Hill announced "Soul2Soul The World Tour 2017" kicking off in New Orleans on April 7th, 2017. The 65-city tour celebrates the 10th anniversary of the record-breaking "Soul2Soul II" tour, the highest-grossing multi-year country music tour of all time, and the first time Faith Hill has toured since 2007. And today, the tour announced two Nashville shows added to the itinerary. See additions in tour routing below.
Check local listings for ticket on-sale details. Nashville tickets will go on-sale Friday, October 28th at 10am local time.
"We have the best fans in the world, who have been with us through our entire journey and we are so excited to celebrate with them by going back on the road and showcasing an exciting new show," said Tim McGraw and Faith Hill. "It's always great when we get to work together and it's been a while since we got to do that."
It was also announced by NBC'S 'THE VOICE', for the first time ever, the show will feature a duo as key advisers this season. Hill and McGraw will prepare artists for the high-stakes knockout rounds airing in October.
Tim McGraw and Faith Hill "SOUL2SOUL THE WORLD TOUR 2017" North American Dates
Check local listings for on-sale information – new shows listed in BOLD
Date City Venue
April 7, 2017 New Orleans, LA Smoothie King Center
April 9, 2017 Tupelo, MS BancorpSouth Arena
April 20, 2017 N. Charleston, SC N Charleston Coliseum
April 21, 2017 Birmingham, AL Legacy Arena at the BJCC
April 22, 2017 Atlanta, GA Philips Arena
April 27, 2017 St. Louis, MO Scottrade Center
April 28, 2017 Louisville, KY KFC Yum! Center
April 29, 2017 Indianapolis, IN* Bankers Life Fieldhouse
May 4, 2017 Newark, NJ Prudential Center
May 5, 2017 Uncasville, CT Mohegan Sun
May 6, 2017 Uncasville, CT Mohegan Sun
May 11, 2017 Tulsa, OK BOK Center
May 12, 2017 Lincoln, NE Pinnacle Bank Arena
May 13, 2017 Oklahoma City, OK Chesapeake Energy Arena
May 18, 2017 Spokane, WA Spokane Arena
May 19, 2017 Bozeman, MT Brick Breeden Fieldhouse
May 20, 2017 Bozeman, MT Brick Breeden Fieldhouse
May 25, 2017 Boise, ID Taco Bell Arena
May 26, 2017 Portland, OR Moda Center
May 27, 2017 Tacoma, WA Tacoma Dome
May 30, 2017 Vancouver, BC Rogers Arena
June 2, 2017 Calgary, AB Scotiabank Saddledome
June 3, 2017 Edmonton, AB Rogers Place
June 4, 2017 Saskatoon, SK SaskTel Centre
June 7, 2017 Winnipeg, MB MTS Centre
June 9, 2017 Sioux Falls, SD Denny Sanford Premier Center
June 10, 2017 Des Moines, IA Wells Fargo Arena
June 15, 2017 Grand Rapids, MI Van Andel Arena
June 16, 2017 Milwaukee, WI BMO Bradley Harris Arena
June 17, 2017 Moline, IL iwireless Center
June 22, 2017 Ottawa, ON Canadian Tire Centre
June 23, 2017 Toronto, ON Air Canada Centre
July 7, 2017 Boston, MA TD Garden
July 14, 2017 Los Angeles, CA STAPLES Center
July 15, 2017 Los Angeles, CA STAPLES Center
July 21, 2017 Glendale, AZ Gila River Arena
July 23, 2017 San Diego, CA Valley View Casino Center
July 28, 2017 Sacramento, CA Golden 1 Center
July 29, 2017 San Jose, CA SAP Center
August 1, 2017 Denver, CO Pepsi Center
August 3, 2017 Little Rock, AR Verizon Arena
August 4, 2017 Nashville, TN Bridgestone Arena
August 5, 2017 Nashville, TN Bridgestone Arena
August 17, 2017 Cleveland, OH Quicken Loans Arena
August 18, 2017 Philadelphia, PA Wells Fargo Center
August 24, 2017 Fargo, ND Fargodome
August 25, 2017 St. Paul, MN Xcel Energy Center
August 26, 2017 St. Paul, MN Xcel Energy Center
August 31, 2017 Chicago, IL Allstate Arena
September 2, 2017 Cincinnati, OH US Bank Arena
September 7, 2017 Columbus, OH Nationwide Arena
September 8, 2017 Detroit, MI The Palace
September 14, 2017 Knoxville, TN Thompson Boling Arena
September 16, 2017 Jacksonville, FL Veterans Memorial Arena
September 21, 2017 Wichita, KS INTRUST Bank Arena
September 22, 2017 Omaha, NE CenturyLink Center
September 23, 2017 Kansas City, MO Sprint Center
September 27, 2017 Salt Lake City, UT Vivint Smart Home Arena
September 29, 2017 Fresno, CA Save Mart Center
September 30, 2017 Bakersfield, CA Rabobank Arena
October 5, 2017 San Antonio, TX AT & T Center
October 6, 2017 Houston, TX Toyota Center
October 7, 2017 Dallas, TX American Airlines Center
October 12, 2017 Pittsburgh, PA PPG Paints Arena
October 13, 2017 Washington, DC Verizon Center
October 14, 2017 Greensboro, NC Greensboro Coliseum
October 19, 2017 Sunrise, FL BB&T Center
October 20, 2017 Tampa, FL Amalie Arena
October 26, 2017 Buffalo, NY KeyBank Center
October 27, 2017 Brooklyn, NY Barclays Center
*If NBA Playoffs create a scheduling conflict, the Indianapolis concert will be moved to April 30, 2017
For more information on the tour, please visit www.Soul2SoulTour.com or visit www.TimMcGraw.com or www.FaithHill.com.


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Pin Up Cosmetics is honored to have our products used on the set of #ifcportlandia #portlandiaseason7 A Huge thank you to @terrilodge and the Portlandia team. @RepostRegramApp – Prepping for our fave girl Nina! Thank you sooo much to Pin Up Cosmetics for our great products! @pinupcosmeticssf #ninasgotyourblushon #portlandias7 #ifcportlandia #rosemoisturuzerisamazing #rosepetalfacecream #portland #sanfrancisco #veganbeauty…
Category: Vegan Cosmetics
Victoria Lyn Beauty -Artisan Group Swag Bag Unboxing
We are thrilled to be apart of the The Artisan Group Swag Bag gifted to Victoria Lyn Beauty. So many wonderful handcrafted treasures including Pin Up Cosmetics Vegan Mineral Blush in Dolce Vita, Vegan Mineral Eye Shadow in Gorgeous and our Vegan Balmshell Bronzer in Tropic Sunset. You can purchase the items gifted to Victoria…
Swag Bag Unboxing | Handmade Etsy Items
Pin Up Cosmetics had an amazing opportunity to gift our Vegan Mineral Blush in Desire & Dolce Vita as well as our Vegan Mineral Foundation to LolaLynn Mitchell in association with The Artisan Group. Pin Up Cosmetics is honored to be among all of the other amazing artisans. #lolalynnmitchell #pinupcosmeticssf #vaganbeauty #handcrafted #mineralmakeup #vegancosmetics #theartisangroup
Megan Hilt Review of Pin Up Cosmetics Vegan Cleansing Grains & Rose Petal Face Cream
Check out this fun review from Megan Hilt about Pin Up Cosmetics Vegan Cleansing Grains and Rose Petal Face Cream. #meganhiltyoutube #rosecream #vegancleansinggrains #pinupcosmeticssf #ecobeauty #naturalbeauty #naturalskincare
Pin Up Cosmetics Rose Petal Face Cream has a New Look!
We are excited to announce our Rose Petal Face Cream has a NEW LOOK designed by Julia Marie Design Studio. Thank you for making our Rose Petal Face Cream our #1 seller. Stop by your local San Francisco Whole Foods Markets or Rainbow Grocery Co-Op and sample our Rose Petal Face Cream. You can…
Check Out Pin Up Cosmetics in Bob Cut Magazine!
We are thrilled we made the Bob Cut Magazine must have list in all beauty categories from skin care to body care and cosmetics. Read all about us and other indie beauty brands. #pinupcosmeticssf #sanfrancisco #veganbeauty #naturalbeauty
Pin Up Cosmetics Lavender & Chamomile Face Cream
Pin Up Cosmetics had an amazing opportunity to gift our Lavender & Chamomile Face Cream to Hayley Segar in association with The Artisan Group. Check out what Hayley Segar had to say about Pin Up Cosmetics and all of the other amazing artisans. #pinupcosmeticssf #vaganbeauty #handcrafted #skincare #theartisangroup #hayleysegar Shop Pin Up Cosmetics Lavender &…
Pin Up Cosmetics Skin Care Sale @Whole Foods Market
Pin Up Cosmetics will be taking part in the Whole Foods Market Skin Care Sale March 18th-20th. All facial care 25% off! Now is your chance to stock up on Pin Up Cosmetics Rose Petal Face Cream, Vegan Cleansing Grains and Grapefruit & Lavender Serum. Stop by and check out our demo and pick up…
Angie Tribeca!
Pin Up Cosmetics received an amazing shout out today from Actress Andree Vermeulen and Celebrity MUA Elizabeth Hoel-Chang of the TBS show Angie Tribeca. See shout out https://www.instagram.com/ehmakeupartist #pinup #pinupgirl #pinupcosmeticssf #adorable #vegan #crueltyfree #makeup #makeupartist #amazing #retro #vintage #beautiful #beauty #bridgetbardot #gorgeous #angietribeca #tbs #naturalcosmetics #veganbeauty
Pin Up Cosmetics Skin Care
Shop Pin Up Cosmetics Skin Care on Amazon. Email us your Amazon receipt and we will send you a free sample of our Grapefruit & Lavender Serum. Email us: email@example.com #amazon #pinupcosmeticssf #rosepetalfacecream #faceandbodycleanser #vegancleansinggrains
Pin Up Cosmetics Vegan Hair Elixir in Lavender and Rose
Have you tried our handcrafted Vegan Hair Elixir? You are going to love our conditioning leave in hair treatment. Nourish and strengthen your hair from root to tip. Contains pure Argan Oil and pure essential oils. Available as a set in rose and lavender. No Parabens, No Petroleum, No Mineral Oil, No Artificial Colors 4oz….
Check Us Out on Youtube
It's been a long time coming but we finally created a Youtube Channel for Pin Up Cosmetics. We are looking for contributes for our Youtube Channel. If you love natural & vegan beauty products please send us an email and tell us about yourself along with links to your work. Email: email@example.com Pin Up Cosmetics…


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Prestigious printmaking conference sees record attendance
The Southern Graphics Council International conference, which is being hosted this week by the University of Wisconsin-Milwaukee and the Milwaukee Institute of Art & Design, has seen the highest attendance in its history.
The annual conference has attracted 2,060 artists from around the world to Milwaukee, said Jessica Meuninck-Ganger, the head of printmaking at UWM's Peck School of the Arts and one of the people who helped attract the conference to Milwaukee. »Read Full Blog Post(1)
Summerfest's new Uline Warehouse stage to feature Jana Kramer, Rick Springfield
The inaugural lineup for Summerfest's new Uline Warehouse stage will include TV-star-turned-country-artist Jana Kramer, Christian-influenced alt-rock group Switchfoot and a pair of newly announced headliners: jam-heavy blues rock group Blues Traveler and '80s power-pop idol and Milwaukee favorite Rick Springfield.
The list of headliners, announced by Summerfest officials Tuesday morning, features: »Read Full Article(2)
Oprah helps her newly found half sister celebrate birthday
In early 2011, Oprah revealed to the world that she had a younger half sister who lived in Milwaukee.
The Associated Press and the Journal Sentinel's Jackie Loohauis-Bennett reported the story of Oprah introducing half sister Pat to the world. »Read Full Article
Details revealed for free Milwaukee concert with Macklemore & Ryan Lewis, Skylar Grey
Additional details have emerged regarding a previously announced Milwaukee show with "Thrift Shop" hitmakers Macklemore & Ryan Lewis and Grammy-nominated Wisconsin native Skylar Grey.
'Lincoln' director Spielberg's new biopic: 'Obama'
The White House Correspondents' Dinner, the annual political roast, is a schmoozy affair, with celebrities like Amy Poehler, Claire Danes from "Homeland" and Kate Mara from "House of Cards" - see a red carpet photo array here - sharing tables with members of the media.
This year's affair - emceed by Conan O'Brien - included self-deprecating and barbed comic remarks from President Barack Obama. Also featured were short video skits, including the one below in which "Lincoln" director Steven Spielberg talked about his next film bio project: "Obama." "The guy's already a lame duck," says Spielberg, "so why wait?" »Read Full Blog Post(3)
Chef's Table event space and restaurant coming to Walker's Point
David Magnasco, the executive chef at the Milwaukee Club, is planning an event space at 500 S. 3rd St. called the Chef's Table that also will be open to the public once a month for multicourse dinners.
The 100-year-old brick building will house the restaurant on the first floor, and the second floor will be home to Magnasco and his wife, Julia, executive director of First Stage children's theater, and their 3-year-old daughter, Maddalena. »Read Full Blog Post(2)
Diana Ross performing at Riverside Theater Aug. 27
Diana Ross fans have good reason for "coming out" to the Riverside Theater this summer.
On Tap for Today: Wine tasting, Brewers and Michael Pollan
Monday is happening this week. Who knew?
You do. »Read Full Blog Post
Summerfest announces U.S. Cellular Connection Stage headliners, including Neon Trees, Alex Clare
Summerfest officials have announced the 2013 headliner lineup for the U.S. Cellular Connection Stage—including recent stage favorites AWOLNATION and Neon Trees—plus performances from Alex Clare, the Neighbourhood and the Features.


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Margarita Blue – Retro Pub Galadari Hotel Sri Lanka
Positioned in a perfect setting, overlooking the Indian Ocean, The Margarita Blue sets the mood for a modern yet cosy atmosphere with splendid views of the sunset from the garden terrace. With live entertainment by "Mirage" from Wednesday to Saturday, it is the perfect hang out or a lover of Retro Music. The pub also offers games such as Darts, Snooker and Pool including the best and latest in sports on a giant screen.
Open from Tuesday to Sunday from 4.00 pm onwards


text:
Hi Guys,
Who will able go to LAX this summer of 2004 with Airliners International 2004? If you will able go to LAX for this summer at Sheraton Hotel. I will able to go into LAX this summer 2004 and probably Eddy Gual will able to go into LAX and just got emailing from him today. Also, there is some of those ramp tour into LGB and it would able good for you with the photography in LGB and but, I couldn't not find one of those ramp tour in LAX either and can you anyone please helped me about information with me? Thanks!


text:
realmagick.com The shrine of knowledge.
Exploit Computer Science
A selection of articles related to exploit computer science.
Original articles from our library related to the Exploit Computer Science. See Table of Contents for further available material (downloadable resources) on Exploit Computer Science.
- Bringing it Down to Earth: A Fractal Approach
- 'Clouds are not spheres, mountains are not cones, coastlines are not circles, and bark is not smooth, nor does lightning travel in a straight line.' B. Mandelbrot W e want to think about the future - it's our nature. Unlike other creatures, humans possess an...
Mystic Sciences >> Astrology
- Question the Premises of Society and Science
- Question the ultimate validity of the basic premises of society, in particular, scientific theory. Do not accept concepts or statements as truthful simply due to weight of tradition or learned opinion. The synthesis of these statements is a healthy skepticism...
Religion & Philosophy >> Philosophy
- Magick and Science
- Many people wonder how magick works. To the non-believer, they say that there is no proof that spells work. And those abilities such as telekinesis are illusionary or product of imagination. They ask us to use scientific means to explain how exactly these...
Mystic Sciences >> Magick
- The Religious Experience: A Wiccan Viewpoint
- What is religion? Religion is a set of beliefs which allow us to understand and categorize our world and our place in it. A set of beliefs which define our culture, our expectations, our views of people and behaviors we expect. I have found several different...
Religion & Philosophy >> Religions
Exploit Computer Science is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Exploit Computer Science books and related discussion.
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- Update: Why this week's man-versus-machine Go match doesn't matter (and what does)
- Today, in the first round of a weeklong match pitting man against machine in the ancient Chinese game of Go, Google's AlphaGo computer program won the first battle. But will any of this matter in the long run? In this story, published Monday, Science ...
- With Boxmate malicious programs have no place left to hide
- No matter how well-tested our software may be, hackers keep on finding vulnerabilities to exploit or control systems at will.
- Hackers in training
- The first-year Massachusetts Institute of Technology PhD student is researching urban planning, not computer science. But last weekend, with more than $20,000 in prize money on the line, Mr. Falco raced two dozen students from MIT and the other famed ...
- Companies Like Facebook Should Pay Attention To What's Happening In Chicago
- "Kids are riveted, they're excited -- they want to do this," Brenda Wilkerson, senior manager of computer science and information technology education at CPS, told The Huffington Post in a recent interview.
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Hopewell Valley homework guidelines
Monday, June 17, 2013 7:50 PM
Kerry Shevlin, 12, left, arrives home after school, followed by her mom, Claire Shevlin and their dog, Riley. Hopewell Valley is introducing homework regulations that set guidelines on required work for students. Michael Mancuso/The Times
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- Princeton schools plan homework-free weekends, joining other districts October 06, 2015, 7:23 PM
- West Windsor-Plainsboro Schools end final and midterm testing October 15, 2015, 5:12 PM


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Write Access
Write Access
DVD Inlay
I just finished reading the latest edition of Linux Magazine. Alas again no DVD box (yes, I read your reply to the customer complaint). I still don't agree, and I'd rather have the DVD box back. I am willing to pay a little extra for the service.
Anyway, could you at least make the covers of the DVD boxes available as a download from your site? Consider it a service to your readers that really want the DVD box (like me). I am going to put the DVDs in a box, and I do want a nice cover with the necessary information in there also. If necessary, I can print the cover myself.
Rob Prikanowski
Thank you for your feedback!
The printable DVD covers are now back by popular demand. You will find the DVD inlays at our website. Visit the following page: http://www.linux-magazine.com/issues or (http://www.linuxpromagazine.com/issues). Click on the picture of the issue for which you'd like to obtain the DVD cover. On the issue page, select the link labeled DVD inlay. Download the PDF image to your desktop.
I am thinking of moving on from the Microsoft monopoly. I currently use Windows ME and XP operating systems; my main worry is a compatibility issue. Is Linux capable of accepting software not designed to run with the linux O/S, for example Microsoft messenger/hotmail? If you say generally OK, how do I start please? I'm looking forward to hearing from you.
Michael Daniels
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Linux Voice Joins the Linux New Media Family
Linux Magazine will include the best of both magazines.
Critical Flaws Found in VeraCrypt
Popular open source encryption tool is vulnerable to attack
Ubuntu 16.10 Released
New "Yakkety Yak" edition emphasizes cloud and servers
Linus Announces Linux 4.8
Google Announces Its Own Pixel Phones
Google finally enters the phone hardware business.
Nextcloud Announces Raspberry Pi-Powered Home Cloud Box
Innovative system adds a hard drive and Ubuntu Core to the RPi for an IoT hub.
Linus Torvalds Confirms the Date of the First Linux Release
Linux is two weeks younger than we thought!
End of OpenOffice?
The Apache Software Foundation considers retiring OpenOffice
Adobe Gives New Life to NPAPI Plugin for Linux
Adobe won't kill the plugin in 2017
LinuxCon North America Convenes in Toronto, Canada
Linux Foundation's big event celebrates the 25th anniversary of Linux


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Imperial (Penn.) West Allegheny athlete Dorin Dickerson went to the Penn State NIKE Camp looking to prove that he could play multiple positions on offense. He left with MVP accolades and a lot of c...
Dorin Dickerson discusses his top five
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Gray Surgical Set to Significantly Expand International Network
Gray Surgical
Gray Surgical Set to Significantly Expand International Network
Gray Surgical has announced that it is plans to enter into a number of mutually beneficial agreements with selected new distributors throughout North America/Europe and Asia.
CEO of Gray Surgical, Mr. Michael C Duff recently stated that "We are looking to aggressively expand our international distributor network. We believe that we manufacture the best table mounted surgical retractors in the world. Therefore it is only logical that we want our products to be represented in every major market in the world.
There are many specialist surgeons in countries where we don't have a presence yet that have not been able to experience the benefits of the patented features and ease of use of our products. We will definitely be bringing our product range to these markets very soon."
Mr. Duff went on to say "It is important to select the right distributors for our products. We look for a well respected company in the medical distribution sector that has an extensive sales force with relevant experience in selling surgical instruments into an operating theatre environment. In return we offer an exclusive distributorship that provides extremely attractive margins for the right distributor. We also provide a full range of electronic marketing materials to promote our product range."
Gray Surgical is keen to enter into negotiations with suitably qualified distributors of surgical instruments for the following regional markets:
1. North America
2. Russia (Moscow)
3. Spain/Portugal
4. Greece/Turkey
5. Austria/Switzerland
6. Netherlands
7. UAE/Saudi Arabia
8. Israel
9. Eastern Europe (Czech, Yugoslavia, Hungary, Poland, Bulgaria)
10. South America
11. South Africa
12. East Asia
13. South East Asia
"Any interested parties are encouraged to contact me either directly at Medica or via the email address below" said Mr. Michael C Duff.
For further information please contact: