To see the other types of publications on this topic, follow the link: The Last Gatekeeper.
Journal articles on the topic 'The Last Gatekeeper'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'The Last Gatekeeper.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Shtivelband, Annette, Patricia A. Aloise-Young, and Peter Y. Chen. "Sustaining the Effects of Gatekeeper Suicide Prevention Training." Crisis 36, no. 2 (2015): 102–9. http://dx.doi.org/10.1027/0227-5910/a000304.
Full textAbstract:
Background: Gatekeeper training is a promising suicide prevention strategy that is growing in popularity. Although gatekeeper training programs have been found to improve trainee knowledge, self-efficacy, and perceived skills, researchers have found that the benefit of gatekeeper training may not last over time. Aims: The purpose of this study was to identify strategies for strengthening the long-term effects of suicide prevention gatekeeper training. Method: In-depth interviews and focus groups were conducted with gatekeepers (N = 44) and data were analyzed using a qualitative research approach. Results: The results of this study suggest that posttraining interventions may be more effective if they include the following seven themes: (a) social network – connecting with other gatekeepers; (b) continued learning – further education; (c) community outreach – building awareness; (d) accessibility – convenience; (e) reminders – ongoing communication; (f) program improvement –- enhancing previous training; and (g) certification – accreditation. Conclusion: Posttraining interventions that incorporate the themes from this study offer a promising direction in which to sustain the effects of gatekeeper suicide prevention training.
2
Johnson, Miriam. "The Power of the Gatekeeper." Logos 31, no. 1 (2020): 27–34. http://dx.doi.org/10.1163/18784712-03101003.
Full textAbstract:
The publishing industry has a variety of gatekeepers that play a role in deciding which works become books. This article acknowledges the main gatekeepers as the agent and publishers, but also draws attention to the author, who is the first gatekeeper, and the reader, who is the last. The connections between gatekeepers highlight the role of power in these positions. Using Foucault’s theories of archaeology and genealogy, this article argues that positions within the industry provide space for the gatekeepers to say what works deserve to be published. In doing so it highlights the dynamic flow of power, which rises from the bottom and provides a hierarchical structure within the industry.
3
Mah, Kate. "The Silent Gatekeeper: Authoritarianism and Civil Society in China." Political Science Undergraduate Review 2, no. 2 (2017): 66–72. http://dx.doi.org/10.29173/psur40.
Full textAbstract:
This paper examines the emergence of civil society in China under the authoritarian system in the last thirty years. It seeks to explore the ways in which an initial, traditional notion of civil society has altered in the context of China, as well as the respective challenges faced by both the organizations and the government in carrying out their goals and governance. The rapid rise of market capitalism, globalization and Chinese economic success in the last forty years to present day has made room for the rise of non-governmental organizations as well as social mobilization and engagement from citizens. This paper suggests that China has been able to accept the emergence of civil society, however, despite these developments, the government has been able to sufficiently suppress civil society from carrying out any objectives of transparency, social justice and accountability. It surveys the history of civil society within the authoritarian state, analyzes the specific government-NGO relations between the Chinese Communist Party and civil society organizations, and reflects upon the implications of the current legal and political framework that Chinese civil society must operate under.
4
Bozanic, Zahn, Preeti Choudhary, and Kenneth J. Merkley. "Securities Law Expertise and Corporate Disclosure." Accounting Review 94, no. 4 (2018): 141–72. http://dx.doi.org/10.2308/accr-52265.
Full textAbstract:
ABSTRACT We examine whether securities lawyers involved in SEC comment letter inquiries act as client advocates by resisting disclosure changes or as gatekeepers by encouraging disclosure transparency. Consistent with an advocacy role, we find that securities lawyers' involvement in SEC comment letters is associated with resisting disclosure inquiries through redacting information from filings and issuing fewer amendments to previous disclosures. Our evidence also supports the view that the role of securities lawyers extends beyond the specific inquiry; their involvement is associated with improved readability and more cautionary language in the subsequent 10-K, and fewer future restatements and comment letters. Last, we find that securities lawyers serve more of an advocacy role when proprietary costs are high and when the inquiry involves a possible amendment, but more of a gatekeeper role when an inquiry is more complex. JEL Classifications: M41
5
Zhan, Hong Jun. "Design and Realization of Network Security Defense Architecture of Medical Information Integration Platform." Applied Mechanics and Materials 411-414 (September 2013): 600–606. http://dx.doi.org/10.4028/www.scientific.net/amm.411-414.600.
Full textAbstract:
In this paper, based on the characteristics of heterogeneous information integration, a set of complete medical information integration platform network security defense architecture was designed by utilizing network security defense equipment and technologies such as gatekeeper, disk array and hot-standby etc. On the basis of overall design, the construction, deployment and operation of related system were realized. At last, the effectiveness of the network security defense architecture designed and realized in this paper was tested by means of fault injection.
6
Carpenter, Charli, Sirin Duygulu, Alexander H. Montgomery, and Anna Rapp. "Explaining the Advocacy Agenda: Insights from the Human Security Network." International Organization 68, no. 2 (2014): 449–70. http://dx.doi.org/10.1017/s0020818313000453.
Full textAbstract:
AbstractThrough a series of focus groups with human security practitioners, we examined how powerful organizations at the center of advocacy networks select issues for attention. Participants emphasized five sets of factors: entrepreneur attributes, adopter attributes, the broader political context, issue attributes, and intranetwork relations. However, the last two were much more consistently invoked by practitioners in their evaluations of specific candidate issues. Scholars of global agenda setting should pay particular attention to how intranetwork relations structure gatekeeper preferences within transnational advocacy spaces because these help constitute perceptions of issues' and actors' attributes in networks.
7
Khan, Harun, Hassan Joudi, and Zahraa Ahmed. "The Muslim Council of Britain: Progressive Interlocutor or Redundant Gatekeeper?" Religions 11, no. 9 (2020): 473. http://dx.doi.org/10.3390/rel11090473.
Full textAbstract:
Since its inception in 1997, the Muslim Council of Britain (MCB) has evolved to become one of the most enduring British Muslim organisations. It is a representative body for over 500 member bodies (‘affiliates’) including mosques, schools and charities. During the course of the last two decades, it has been subject to external comment and sometimes critique by academics, media commentators, policy-makers, and others. This special issue of the journal Religions has provided a welcome opportunity for the current leadership of the MCB to write about the organisation from ‘within’, based on their long-standing time volunteering with it. This paper is based on an oral history methodology involving extended interviews with the oversight of a research director, supplemented by reference to existing academic and other sources. Therefore this paper is essentially a type of ‘edited transcript’ aggregated wholly from a series of first person interviews undertaken with the current senior elected leaders of MCB; reorganised for clarity and drafted out with added ‘prose’ allowing for it to be presented in essay form. The result is the first documented ‘insider’ perspective on the ways in which the MCB has tackled issues such as internal governance, the challenge of ‘representation’ in view of the diversity of British Muslim communities, changing relationships with government, and policy work. It becomes apparent through the paper that the MCB has matured into a constructively self-critical, pro-active, and more strategically professional body, that contributes to the flourishing of Muslim communities and the place of Islam in British society. The production of the paper is itself an indicator of the growing confidence and capacity of the MCB, and its ability to contribute positively to academic discourse and debate about Muslims in Britain.
8
Tidrow, Thierry. "Olga Neuwirth, Orlando. Wiener Staatsoper, December 2019." Tempo 74, no. 293 (2020): 84–85. http://dx.doi.org/10.1017/s0040298220000030.
Full textAbstract:
The Vienna State Opera made headlines around the world last December, boasting that it had finally commissioned a full-scale opera by a female composer. Olga Neuwirth, known for her difficult, unrestrained character (both musical and personal), was a curious and adventurous choice for the Wiener Staatsoper, the embassy of a conservative cultural landscape and gatekeeper of highbrow art. Choosing Virginia Woolf's seminal novel about a poet who lives through the ages and who one day miraculously changes sexes was a fitting choice for this maverick, whose work blurs the lines between genius – in all its anachronistic complexities – and fremdschämend, the well-established German equivalent of the facepalm, always scoring particularly high on listicles of ‘quintessential German words’.
9
Llewelyn, Stephen R., Gareth J. Wearne, and Bianca L. Sanderson. "Guarding Entry to the Kingdom: The Place of Eunuchs in Mt. 19.12." Journal for the Study of the Historical Jesus 10, no. 3 (2012): 228–46. http://dx.doi.org/10.1163/17455197-01003002.
Full textAbstract:
The article argues that, contrary to the majority view, the metaphor of the eunuch in Mt. 19.12 should be understood against the backdrop of the royal eunuch, as encountered in story, if not in experience. As such the saying must be situated with other sayings that speak of entry to the Kingdom. The change of the metaphor’s focus from that of guardian/gatekeeper to that of sexualized trope, as it is now met in Matthew, was facilitated by the saying’s performance to a new audience, i.e. to a Greek-speaking rather than Semitic-speaking audience. At the same time the saying was repunctuated to idealize the last class of eunuch who now became the model of chastity within the ekklesia.
10
Edison, Edison, and Reski Pulpi Tambes. "Peran Editor Video Dalam Produksi Program Sembang Malam di Ceria TV Pekanbaru." An-Nida' 43, no. 1 (2021): 15. http://dx.doi.org/10.24014/an-nida.v43i1.9378.
Full textAbstract:
AbstactMass communication must be adjacent to gatekeeper, referred to as gatekeeper in an assignment i.e. the person in charge of selecting, choosing, changing, responsible later on to a will be broadcast to audiences. At CeriaTV Pekanbaru Video Editor is the role holder of gatekeeper, because the video editor in CeriaTV Pekanbaru that will answer the results of the editing later and the creativity of an editor can add the selling value of a program that is edited and presented later to the audience. CeriaTv Pekanbaru still has a shortage of human resources, then the production Director, the documentation division can concurrently become an editor. The research aims to find out how the video Editor role in the production of Sembang Malam program at CeriaTV Pekanbaru. The subject of this study is CeriaTv Pekanbaru and the object of this research is the role of editors in the production of a Sembang Malam program at CeriaTV Pekanbaru. This research uses qualitative descriptive research methods. The results of the editor's role through the first three stages, the first offline editing stage, at this stage an editor can play a role in shooting with a cameraman whose goal is to know the picture during the editing process later, and data checking. Further more the online editing stage, at this stage an editor checks equipment on the editing equipment, has its own notes for editing (according to the script), content and video visuals, editors must have the creativity issued When content editing and video visuals take place. The last stage is mixing (merging between sound and video), at this stage the sound and video must be balanced and at this stage also there are additional sounds such as sound effect, and backsound if needed. From these three stages, an editor can produce programs, both and interestingly the program is in the editor and creativity of the editors package the program, hence the editor is very important to manage the program that will be aired on audiences. Talk show-based Sembang Malam programmes that cover the hottest things, as well as inviting guest stars that inspire, from communities and individuals.
11
Williams, Mandy, and Allal Ouhtit. "Towards a Better Understanding of the Molecular Mechanisms Involved in Sunlight-Induced Melanoma." Journal of Biomedicine and Biotechnology 2005, no. 1 (2005): 57–61. http://dx.doi.org/10.1155/jbb.2005.57.
Full textAbstract:
Although much less prevalent than its nonmelanoma skin cancer counterparts, cutaneous malignant melanoma (CMM) is the most lethal human skin cancer. Epidemiological and biological studies have established a strong link between lifetime exposure to ultraviolet (UV) light, particularly sunburn in childhood, and the development of melanoma. However, the specific molecular targets of this environmental carcinogen are not known. Data obtained from genetic and molecular studies over the last few years have identified the INK4a/ARF locus as the “gatekeeper” melanoma suppressor, encoding two tumour suppressor proteins in human, p16INK4aand p14ARF. Recent developments in molecular biotechnology and research using laboratory animals have made a significant gene breakthrough identifying the components of the p16p16INK4a/Rb pathway as the principal and rate-limiting targets of UV radiation actions in melanoma formation. This review summarizes the current knowledge of the molecular mechanisms involved in melanoma development and its relationship to sunlight UV radiation.
12
Lo, Chih Hung, Tory M. Schaaf, Benjamin D. Grant, et al. "Noncompetitive inhibitors of TNFR1 probe conformational activation states." Science Signaling 12, no. 592 (2019): eaav5637. http://dx.doi.org/10.1126/scisignal.aav5637.
Full textAbstract:
Tumor necrosis factor receptor 1 (TNFR1) is a central mediator of the inflammatory pathway and is associated with several autoimmune diseases such as rheumatoid arthritis. A revision to the canonical model of TNFR1 activation suggests that activation involves conformational rearrangements of preassembled receptor dimers. Here, we identified small-molecule allosteric inhibitors of TNFR1 activation and probed receptor dimerization and function. Specifically, we used a fluorescence lifetime–based high-throughput screen and biochemical, biophysical, and cellular assays to identify small molecules that noncompetitively inhibited the receptor without reducing ligand affinity or disrupting receptor dimerization. We also found that residues in the ligand-binding loop that are critical to the dynamic coupling between the extracellular and the transmembrane domains played a key gatekeeper role in the conformational dynamics associated with signal propagation. Last, using a simple structure-activity relationship analysis, we demonstrated that these newly found molecules could be further optimized for improved potency and specificity. Together, these data solidify and deepen the new model for TNFR1 activation.
13
Costanza, Massimo, and Gaetano Finocchiaro. "Allergic Signs in Glioma Pathology: Current Knowledge and Future Perspectives." Cancers 11, no. 3 (2019): 404. http://dx.doi.org/10.3390/cancers11030404.
Full textAbstract:
Historically restrained to immune defense against parasite infections, allergic inflammation has been recently rediscovered to protect from a wide array of environmental triggers, such as xenobiotics and carcinogens, which can induce DNA damage and ultimately lead to cancer development. Moreover, cells and mediators typical of allergic responses can importantly modulate the tissue inflammatory milieu, which represents a crucial gatekeeper towards the acquisition of malignancy by cancer cells through immune escape. Numerous studies have described an inverse association between allergies and glioma development. Mast cells, key players of allergic reactions, have been recently found at increased numbers in glioblastoma multiforme (GBM), the most common and lethal primary brain tumor, and they have been implicated in GBM pathogenesis. In this review, we summarize epidemiological studies and discuss the main evidence highlighting a potential interplay between allergic responses, and glioma formation and progression. Last, we draw future lines of research for better clarification whether and through which mechanisms allergic inflammation might impact on gliomagenesis. The comprehension of the immune mechanisms favoring or counteracting tumor growth might open the path to novel immunotherapy approaches.
14
Lukasz, Alexander, Philipp Kümpers, and Sascha David. "Role of Angiopoietin/Tie2 in Critical Illness: Promising Biomarker, Disease Mediator, and Therapeutic Target?" Scientifica 2012 (2012): 1–8. http://dx.doi.org/10.6064/2012/160174.
Full textAbstract:
Critical illness is a descriptive, broad term for a serious clinical condition that can result from enormously heterogeneous etiologies. A common end feature these patients regularly suffer from is the so-called multiple organ dysfunction syndrome (MODS), often a consequence of organ hypoperfusion and ischemia, coagulopathies, overwhelming inflammatory responses, immune paralysis and mitochondrial dysfunction. Mechanistically, endothelial injury and particularly microvascular leakage is a major step in the pathophysiology of MODS and contributes to its mortality. The angiopoietin (Angpt)/Tie2 system consists of the endothelial tyrosine kinase Tie2 and its 4 circulating ligands (Angpt1-4). The balance between the agonistic ligand “Angpt-1" and the antagonistic one “Angpt-2" regulates baseline endothelial barrier function and its response to injury and is therefore considered a gatekeeper of endothelial activation. This paper provides a systematic overview of the Angpt/Tie2 system with respect to (1) its role as a global biomarker of endothelial activation in critical ill patients, (2) its contribution to MODS pathophysiology as a disease mediator, and last but not least (3) putative therapeutic applications to modify the activation state of Tie2 in mice and men.
15
Galal, Osman M., and Judie Hulett. "Obesity among Schoolchildren in Developing Countries." Food and Nutrition Bulletin 26, no. 2_suppl2 (2005): S261—S266. http://dx.doi.org/10.1177/15648265050262s217.
Full textAbstract:
The threat of worldwide obesity in children is a reality and has become pandemic. Previously a concern of only developed countries, rapid, escalating rates of overweight children now dominate the public health concerns of middle-and low-income nations as well. There are, of course, many influences that have literally shaped the global population, but there is also a recent observable pattern that is shared by those developing countries with increasingly obese children: a grand structural shift in diet and activity levels on every continent and in every region has occurred in the last quarter century, accompanied by rising rates of obesity. Two central public health concerns drive the need for effective interventions: the immediate health of children and the imminently crushing blow that is coming to health care systems and developing economies due to high rates of chronic disease. In developed nations, the role of gatekeeper has shifted to childcare providers, media, and schools, but in the developing world the traditional role of the mother as home manager has remained intact. Accepting the mother as the primary care provider within the child's nuclear environment places the mother as the guardian of the family's resources, which may be a viable alternative to the types of health-promotion efforts found in past ineffective models.
16
Malacaria, Eva, Masayoshi Honda, Annapaola Franchitto, Maria Spies, and Pietro Pichierri. "Physiological and Pathological Roles of RAD52 at DNA Replication Forks." Cancers 12, no. 2 (2020): 402. http://dx.doi.org/10.3390/cancers12020402.
Full textAbstract:
Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It is also an Achille’s heel of cancer. Thus, identification of pathways used by the cancer cells to respond to replication-stress may assist in the identification of new biomarkers and discovery of new therapeutic targets. Alternative mechanisms that act at perturbed DNA replication forks and involve fork degradation by nucleases emerged as crucial for sensitivity of cancer cells to chemotherapeutics agents inducing replication stress. Despite its important role in homologous recombination and recombinational repair of DNA double strand breaks in lower eukaryotes, RAD52 protein has been considered dispensable in human cells and the full range of its cellular functions remained unclear. Very recently, however, human RAD52 emerged as an important player in multiple aspects of replication fork metabolism under physiological and pathological conditions. In this review, we describe recent advances on RAD52’s key functions at stalled or collapsed DNA replication forks, in particular, the unexpected role of RAD52 as a gatekeeper, which prevents unscheduled processing of DNA. Last, we will discuss how these functions can be exploited using specific inhibitors in targeted therapy or for an informed therapy selection.
17
Bos, Michael. "HEALTH TECHNOLOGY ASSESSMENT IN THE NETHERLANDS." International Journal of Technology Assessment in Health Care 16, no. 2 (2000): 485–519. http://dx.doi.org/10.1017/s0266462300101126.
Full textAbstract:
The Dutch healthcare system is not a single overall plan, but has evolved from a constantly changing mix of institutions, regulations, and responsibilities. The resulting system provides high-quality care with reasonable efficiency and equal distribution over the population. Every Dutch citizen is entitled to health care. Health insurance is provided by a mix of compulsory national insurance and public and private insurance schemes. Hospitals generally have a private legal basis but are heavily regulated. Supraregional planning of high-tech medical services is also regulated. Hospitals function under fixed, prospective budgets with regulation of capital investments. Independent general practitioners serve a gatekeeper role for specialist and hospital services and are paid by capitation or fee for service. Specialists are paid by fee for service. All physicians' fees are controlled by the Ministry of Economic Affairs. Coverage of benefits is an important method of controlling the cost of services. There is increasing concern about health care quality. Health technology assessment (HTA) has become increasingly visible during the last 15 years. A special national fund for HTA, set up in 1988, has led to many formal and informal changes. HTA has evolved from a research activity into policy research for improving health care on the national level. In 1993 the government stated formally that enhancing effectiveness in health care was one of its prime targets and that HTA would be a prime tool for this purpose. The most important current issue is coordination of HTA activities, which is now undertaken by a new platform representing the important actors in health care and HTA.
18
Liu, Tian, Yiwei Wang, Yubing Wang, and Andrew M. Chan. "Multifaceted Regulation of PTEN Subcellular Distributions and Biological Functions." Cancers 11, no. 9 (2019): 1247. http://dx.doi.org/10.3390/cancers11091247.
Full textAbstract:
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene frequently found to be inactivated in over 30% of human cancers. PTEN encodes a 54-kDa lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase pathway involved in the promotion of multiple pro-tumorigenic phenotypes. Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer’s disease, and autism spectrum disorders. This finding suggests that diverse cell types, especially differentiated cells, express PTEN. At the cellular level, PTEN is widely distributed in all subcellular compartments and organelles. Surprisingly, the cytoplasmic compartment, not the plasma membrane, is the predominant subcellular location of PTEN. More recently, the finding of a secreted ‘long’ isoform of PTEN and the presence of PTEN in the cell nucleus further revealed unexpected biological functions of this multifaceted molecule. At the regulatory level, PTEN activity, stability, and subcellular distribution are modulated by a fascinating array of post-translational modification events, including phosphorylation, ubiquitination, and sumoylation. Dysregulation of these regulatory mechanisms has been observed in various human diseases. In this review, we provide an up-to-date overview of the knowledge gained in the last decade on how different functional domains of PTEN regulate its biological functions, with special emphasis on its subcellular distribution. This review also highlights the findings of published studies that have reported how mutational alterations in specific PTEN domains can lead to pathogenesis in humans.
19
Fu, Julie, Jenica Upshaw, Michael J. Kelly, et al. "Assessing the Risk of Cardiac Toxicity after Contemporary Treatment for Hodgkin Lymphoma (HL): A Multidisciplinary Systematic Review." Blood 128, no. 22 (2016): 3564. http://dx.doi.org/10.1182/blood.v128.22.3564.3564.
Full textAbstract:
Abstract Introduction: HL is highly curable, with overall survival (OS) rates of approximately 85-90%. A primary goal of treating patients is to optimize disease control while minimizing late effects. Compared to chemotherapy alone, combined modality therapy improves 1-3 year progression free survival by approximately 5% with equivalent OS rates. Cardiovascular late effects are the leading non-malignant cause of death among survivors; however, there remains considerable uncertainty regarding long-term cardiac risk from contemporary therapy. To help provide the framework for informed decisions, we conducted a systematic review to estimate cardiovascular late effects after HL treatment. We sought studies focused on patients who had received contemporary treatment regimens and on cardiac outcomes important to providers and patients. Methods: Our multidisciplinary study team, including pediatric and adult hematologists, a cardiologist, and decision experts, systematically reviewed the published literature. We searched MEDLINE/PubMed (from inception-December 30, 2015) and the Cochrane Database of Systematic Reviews (from 2005-December 30, 2015). Our search combined specific MeSH and text words using the following search groups: HL, cardiovascular outcomes, treatment related terms and cardiac outcome-specific terms. We included only articles published after 1990 as the mid-1990s saw both a shift away from mantle radiation and the incorporation of anthracyclines. We also conducted a citation analysis of review articles. We included abstracts of studies of human subjects with HL if they reported cardiac toxicity after treatment. We excluded abstracts of studies published prior to 1990, with follow up < 5 years post initial treatment completion, with 10 or fewer subjects, studies of relapse treatment, studies for which full text was not in English, and letters and editorials. For retained abstracts, we then performed a "gatekeeper" full text review to identify which studies reported information needed to estimate individual cardiac risk. We retained articles if (1) they reported HL-patient specific results, (2) at least half of the study's HL patients received their initial treatment during the "contemporary" era (post 1990); and (3) they reported cardiac outcomes. We then evaluated studies passing gatekeeper review to determine if (1) they reported clinically relevant cardiac outcomes; and (2) it was possible to calculate rates for outcomes of interest. Results: We identified 523 abstracts and excluded 374. Of the 149 remaining articles, we excluded 55 reviews, leaving 94 for full text review. We excluded 78 studies based on our gatekeeper criteria, leaving 16 articles. We excluded 14 of these 16 articles, in some cases for multiple reasons, including the absence of clinically relevant cardiac outcomes and design limitations making individual risk estimation not possible. Our initial systematic review therefore identified only 2 studies that satisfied all criteria1, 2. Finally, we reassessed the 94 articles satisfying our abstract inclusion criteria. We found that although we could not estimate individual late effect cardiac risk following contemporary HL treatment from results for 92 of these studies, obtaining the primary data would likely make such estimation possible. We identified studies reporting relevant cardiac outcomes with approximately ≥ 100 HL patients who had received contemporary therapy. Conclusion: Our systematic review identified only 2 studies reporting results that could be used to estimate contemporary treatment cardiac late effects. Even papers published within the last 5 years often did not report separate results for patients receiving contemporary vs. early therapies. We are now seeking to obtain and pool patient data across international datasets to estimate risks for multiple cardiac outcomes. Risk assessment will help guide patient-centered discussions by predicting cardiovascular toxicity for HL patients treated with modern therapy. References: 1. Aviles A, Neri N, Nambo M, et al. Late cardiac toxicity secondary to treatment in Hodgkin's disease. A study comparing doxorubicin, epirubicin and mitoxantrone in combined therapy. Leuk Lymphoma 2005; 46 (7): 1023-1028. 2. Galper SL, Yu JB, Mauch PM et al. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011;117(2):412-418. Disclosures Cohen: Joshua Cohen receives support from companies that develop and market medical therapies, some of which may relate to the subject of this abstract.: Consultancy. Evens:Takeda: Other: Advisory board.
20
de Boer, H. J., D. M. Roche, H. Renssen, and S. C. Dekker. "Two-signed feedback of cross-isthmus moisture transport on glacial overturning controlled by the Atlantic warm pool." Climate of the Past Discussions 7, no. 6 (2011): 3859–93. http://dx.doi.org/10.5194/cpd-7-3859-2011.
Full textAbstract:
Abstract. This paper studies the control of the Atlantic Warm Pool (AWP) on atmospheric moisture transport across the Central American isthmus as a potential feedback on rapid glacial climate fluctuations. Defined as a region of the Atlantic with surface temperatures above 28.5 °C, the modern AWP expands from the tropical Northwest Atlantic up to the Gulf of Mexico during boreal summer. Due to enhanced deep convection over these warm waters, changes in AWP area cause inverse changes in the strength of the Caribbean low level jet. This low level jet drives atmospheric moisture transport from the Atlantic across the Central American isthmus towards the Pacific. Changes in cross-isthmus moisture transport, potentially related to the AWP, may therefore have affected North Atlantic salinity and the partly density driven Atlantic Meridional Overturning Circulation (AMOC) during the glacial. Based on available proxy evidence we hypothesize that the AWP evolved independent of extratropical North Atlantic temperatures during most of the last glacial, except during periods of AMOC collapse when intense extratropical North Atlantic cooling may have limited eastward AWP expansion. We investigate the implications of this hypothesis for cross-isthmus moisture transport by simulating the coupled ocean-atmosphere response to AMOC collapse and the atmospheric sensitivity to additional variations in AWP area. Our simulations suggest that a decrease in AWP area may increase cross-isthmus moisture transport, whereas extratropical North Atlantic cooling beside a persistent AWP may decrease cross-isthmus moisture transport. Interpretation of these effects throughout an idealized Bond Cycle suggests a positive feedback of reduced cross-isthmus moisture transport in response to Greenland cooling prior to AMOC collapse. During AMOC collapse, when AWP expansion is proposed to have been inhibited, this positive feedback turns negative as enhanced cross-isthmus moisture transport may help AMOC recovery. Supported by reconstructed sea surface salinity changes, we propose that the AWP may have played a key role in the glacial climate by acting as a gatekeeper to regulate moisture transport across the Central American isthmus.
21
Dhingra, Richa, Manav Malhotra, Vivek Sharma, T. R. Bhardwaj та Neelima Dhingra. "Exploration of Novel 5α-Reductase Inhibitors for Benign Prostatic Hyperplasia by 2D/3D QSAR, Cytotoxicity Pre-ADME and Docking Studies". Current Topics in Medicinal Chemistry 18, № 32 (2019): 2816–34. http://dx.doi.org/10.2174/1568026619666190119145959.
Full textAbstract:
Background: 5α-Reductase (5AR), an NADPH dependent enzyme, is expressed in most of the prostate epithelial cells. By converting testosterone (T) into more potent androgen dihydrotestosterone (DHT), it plays an important role in men physiology and represents an efficient therapeutic target for androgen-dependent diseases. Over the last few years, significant efforts have been made in order to develop 5AR inhibitors (5ARI) to treat Benign Prostatic Hyperplasia because of excessive production of DHT. Methods: In the present study, 2D and 3D QSAR pharmacophore models have been generated for 5ARI based on known IC50 values with extensive validations. The four featured 2D pharmacophore based PLS model correlated the topological interactions (SsOHE-index); semi empirical (Quadrupole2) and physicochemical descriptors (Mol. Wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and has the highest correlation coefficient (r2 = 0.98, q2 =0.84; F = 57.87, pred r2 = 0.88). Internal and external validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic field effects and steric interactions generated by 3D-QSAR showed interesting results in terms of internal and external predictability. The well-validated 2D PLS, and 3D kNN models were used to search novel 5AR inhibitors with different chemical scaffold. The compounds were further sorted by applying ADMET properties and in vitro cytotoxicity studies against prostate cancer cell lines PC-3. Molecular docking studies have also been employed to investigate the binding interactions and to study the stability of docked conformation in detail. Results: Several important hydrophobic and hydrogen bond interactions with 5AR lead to the identification of active binding sites of 4AT0 protein in the docked complex, which include the gatekeeper residues ALA 63A (Chain A: ALA63), THR 60 A (Chain A: THR60), and ARG 456 A (Chain A: ARG456), at the hinge region. Conclusion: Overall, this study suggests that the proposed compounds have the potential as effective inhibitors for 5AR.
22
Jiang, Yinghua, Ning Liu, Qingzhi Wang, et al. "Endocrine Regulator rFGF21 (Recombinant Human Fibroblast Growth Factor 21) Improves Neurological Outcomes Following Focal Ischemic Stroke of Type 2 Diabetes Mellitus Male Mice." Stroke 49, no. 12 (2018): 3039–49. http://dx.doi.org/10.1161/strokeaha.118.022119.
Full textAbstract:
Background and Purpose— The complexity and heterogeneity of stroke, as well as the associated comorbidities, may render neuroprotective drugs less efficacious in clinical practice. Therefore, the development of targeted therapies to specific patient subsets has become a high priority in translational stroke research. Ischemic stroke with type 2 diabetes mellitus has a nearly double mortality rate and worse neurological outcomes. In the present study, we tested our hypothesis that rFGF21 (recombinant human fibroblast growth factor 21) administration is beneficial for improving neurological outcomes of ischemic stroke with type 2 diabetes mellitus. Methods— Type 2 diabetes mellitus db/db and nondiabetic genetic control db/+ mice were subjected into permanent focal ischemia of distal middle cerebral artery occlusion, we examined the effects of poststroke administration with rFGF21 in systemic metabolic disorders, inflammatory gatekeeper PPARγ (peroxisome proliferator-activated receptor γ) activity at 3 days, mRNA expression of inflammatory cytokines and microglia/macrophage activation at 7 days in the perilesion cortex, and last neurological function deficits, ischemic brain infarction, and white matter integrity up to 14 days after stroke of db/db mice. Results— After permanent focal ischemia, diabetic db/db mice presented confounding pathological features, including metabolic dysregulation, more severe brain damage, and neurological impairment, especially aggravated proinflammatory response and white matter integrity loss. However, daily rFGF21 treatment initiated at 6 hours after stroke for 14 days significantly normalized systemic metabolic disorders, rescued PPARγ activity decline, inhibited proinflammatory cytokine mRNA expression, and M1-like microglia/macrophage activation in the brain. Importantly, rFGF21 also significantly reduced white matter integrity loss, ischemic brain infarction, and neurological function deficits up to 14 days after stroke. The potential mechanisms of rFGF21 may in part consist of potent systematic metabolic regulation and PPARγ-activation promotion-associated antiproinflammatory roles in the brain. Conclusions— Taken together, these results suggest rFGF21 might be a novel and potent candidate of the disease-modifying strategy for treating ischemic stroke with type 2 diabetes mellitus.
23
Smith, Catherine C., Mark J. Levis, Alexander E. Perl, et al. "Emerging Mutations at Relapse in Patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial." Blood 134, Supplement_1 (2019): 14. http://dx.doi.org/10.1182/blood-2019-122620.
Full textAbstract:
Introduction: The phase 3 ADMIRAL trial demonstrated that gilteritinib, a novel, potent, oral FLT3 inhibitor, significantly prolonged overall survival and resulted in higher remission rates compared with salvage chemotherapy in patients with FLT3-mutation-positive (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML; Perl AE, et al. AACR 2019), even in the presence of common co-occurring AML mutations (DNMT3A, NPM1, and WT1) (Levis MJ, et al. J Clin Oncol. 2019;37[suppl 15]:7000). However, as with other FLT3 inhibitors, patients often develop resistance after an initial response to gilteritinib. Evidence suggests that expansion of leukemic clones containing mutations in Ras/MAPK pathway genes NRAS and KRAS mediates secondary resistance to gilteritinib in patients with FLT3mut+ R/R AML, and confirms that cells with Ras/MAPK pathway mutations are FLT3mut+ (McMahon CM, et al. Cancer Discov. 2019; doi: 10.1158/2159-8290). We evaluated emerging mutations in patients who relapsed while receiving gilteritinib therapy in the ADMIRAL trial. Methods: Blood or bone marrow samples were available for 361 patients at baseline (97.3% of the intention-to-treat population [N=371]) and for 40 patients who relapsed on gilteritinib treatment. Samples were analyzed by next-generation sequencing using the Archer Core Myeloid Panel. Data were analyzed using Archer Analysis software; the variant allele frequency (VAF) cutoff was ≥2.7%. Results: Of 371 patients enrolled in the ADMIRAL trial, 247 were assigned to 120-mg/day gilteritinib and 75 (30.5%) relapsed during the study. Most relapses (n=72/75; 96.0%) occurred ≤4 weeks from the last gilteritinib dose. Forty patients who had samples available at baseline also had samples at relapse for comparison. No samples were available from patients who relapsed on chemotherapy. At relapse, 27/40 patients (67.5%) had new mutations, including mutations in Ras/MAPK pathway genes (n=18), FLT3 (n=6), WT1 (n=3), IDH1 (n=1), and GATA2 (n=1) (Table). Thirteen patients (32.5%) had no new mutations. Of the 18 patients with Ras/MAPK pathway gene mutations at relapse, 11 (61.1%) had &gt;1 new mutation at relapse (range, 2-6). The most frequently mutated Ras/MAPK pathway gene was NRAS (n=11). Patients were also assessed for Ras/MAPK gene pathway mutations prior to gilteritinib therapy. Among all FLT3mut+ patients analyzed for co-mutated genes at baseline (n=361), 25 (6.9%) had Ras/MAPK pathway gene mutations detected (gilteritinib, n=18; salvage chemotherapy, n=7; median VAF, 13% [range, 3.4%-50%]). In contrast to the 12.0% of patients (n=3/25) who had &gt;1 Ras/MAPK pathway gene mutation at baseline, 61.1% (n=11/18) had &gt;1 Ras/MAPK pathway gene mutation at relapse. Notably, a considerable number of gilteritinib-treated patients who had Ras/MAPK pathway gene mutations at baseline achieved remission: the rate of CRc (ie, composite complete remission: complete remission [CR] or CR with incomplete hematologic/platelet recovery) was 38.9% (n=7/18); the rate of CR/CRh (ie, CR or CR with partial hematologic recovery) was 27.8% (n=5/18). Six patients acquired new FLT3 mutations at relapse. Five of these six patients acquired a F691L gatekeeper mutation; one of these five patients also acquired a FLT3 juxtamembrane domain point mutation. Of the three patients who acquired a WT1 mutation at relapse, one also acquired a FLT3 F691L gatekeeper mutation. The acquisition of Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations at relapse was mutually exclusive. Conclusions: In patients with FLT3mut+ R/R AML who relapsed on gilteritinib therapy, Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations were the most common mutational events. The presence of a Ras/MAPK pathway gene mutation at baseline did not preclude benefit from gilteritinib therapy, possibly due to fewer Ras/MAPK pathway gene mutations per patient at baseline than at relapse. The acquisition of multiple Ras/MAPK pathway gene mutations at relapse likely mediates continued engagement of Ras/MAPK signaling in patients with FLT3mut+ R/R AML receiving gilteritinib. The frequency of emergent FLT3 F691 gatekeeper mutations at relapse in patients who received 120-mg/day gilteritinib in the ADMIRAL study was similar to that observed in relapsed patients who received 20- to 450-mg/day gilteritinib (Levis MJ, et al. Blood. 2017;130[suppl 1]:2705). Table Disclosures Smith: Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding. Levis:Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Daiichi Sankyo Inc: Consultancy, Honoraria. Perl:Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; BioMed Valley Discoveries: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Roche: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Janssen: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant. Berman:Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Abbvie: Research Funding; Astellas: Research Funding; Al Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Yokoyama:Astellas: Other: Travel expenses. Recher:Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yoon:MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Janssen: Consultancy; Genentech, Inc.: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Novartis: Consultancy, Honoraria. Hill:Astellas: Employment; Ligacept, LLC.: Other: Stock, Patents & Royalties. Rosales:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties.
24
Garbo, Lorenzo. "ADAM SMITH’S LAST TEACHINGS: DIALECTICAL WISDOM." Journal of the History of Economic Thought 38, no. 1 (2016): 41–54. http://dx.doi.org/10.1017/s1053837215000759.
Full textAbstract:
This paper focuses on the teachings and admonitions regarding wisdom found in the sixth edition of Adam Smith’s Theory of Moral Sentiments (TMS). Following a mind-path marked by the seminal contributions of Glenn Morrow (1923), Donald Winch (1978), and Laurence Dickey (1986), the paper offers an interpretation of the higher moral standard (superior prudence) introduced by Smith in the last edition of TMS, as his response to the socio-economic and cultural changes that took place in Great Britain in the second half of the eighteenth century. Between the first and last editions of TMS the taste for luxury and conspicuous consumption became widespread and contagious both geographically and across ranks. Prudence and other-approbation, sufficient gatekeepers of moral conduct and character in the previous editions of TMS, became progressively less effective in keeping society away from moral deception and in regulating reputation and the distinction of ranks. The paper examines the introduction of superior prudence in the last edition of TMS as Smith’s vision of a dialectical process between external and internal approbation that is capable of transforming individual dependence on social praise into a dialogue between materialistic and moral concerns, which would lead to a progressively wiser, although conflictual, existence.
25
MINTO, Andrea. "Enlisting Internal and External Financial Gatekeepers: Problems of Multiple Centres of Knowledge Construction." European Journal of Risk Regulation 9, no. 2 (2018): 283–309. http://dx.doi.org/10.1017/err.2018.13.
Full textAbstract:
AbstractOver the last decade complexity has impaired financial regulators’ and supervisors’ ability to cope with informational asymmetries, moral hazards and other market failures. Recent regulatory responses have been to include external auditors in the range of “gatekeepers” and “watchdogs” that serve regulatory objectives. On the other hand, the compliance function gained greater prominence as a form of internalised law enforcement, being increasingly seen as facilitating the achievement of public regulatory needs in maintaining the safety and soundness of financial institutions. Yet, uncertainty has pervaded the issue of what modes of interaction supervisors, compliance and external auditors should be subject to. International experience and anecdotal evidence show, in fact, that the current informal, discretion-based, relationship between such gatekeepers brings about risks of knowledge fragmentation and ambiguity, calling for better gathering and use of “gatekeepers’ knowledge”. The objective of this article is to address and rectify problems of multiple centres of knowledge construction, by approaching questions pertaining to the interaction between the “internal” and “external” gatekeepers. A primary contribution of this article is to examine this problem by reconciling the strand of research concerning multiple gatekeepers´ liability and the developing legal scholarship on compliance as a delegated form of external enforcement. The explanatory nature of multiple gatekeepers’ liability is twofold: first, it contributes in emphasising the complexity stemming from the interactions between multiple gatekeepers; second, it offers a solid working hypothesis to detect the market failures that can arise from such complexity, namely relating to fragmentation – and construction – of knowledge.
26
Angeli, Franca, Russell Wyborski, Bill Chen, Rama Mallampalli, and Michael Lark. "P157 FBXO3-FBXL2 AXIS MODULATORS AS A NOVEL CLASS OF ORAL SMALL MOLECULE COMPOUNDS FOR THE TREATMENT OF CROHN’S DISEASE." Inflammatory Bowel Diseases 26, Supplement_1 (2020): S6. http://dx.doi.org/10.1093/ibd/zaa010.014.
Full textAbstract:
Abstract Background Ubiquitination is a common post-translational modification, tagging proteins for degradation. The ubiquitin proteasome system is activated in Crohn’s Disease (CD), and modulation of its components might be a novel strategy for therapeutic intervention to control inflammation. The conjugation of ubiquitin to a target protein is orchestrated by a series of enzymatic reactions, the last step being catalyzed by a selective ubiquitin E3 ligase. Among ubiquitin E3 ligases, Fbxl2 serves as a sentinel gatekeeper to limit inflammation by targeting and enhancing the degradation of tumor necrosis factor receptor associated factors (TRAF) proteins, which link cell surface signals (through NFkB signaling) to cytokine secretion. In addition, Fbxl2 controls the ubiquitination of the inflammasome, NOD-like receptor protein 3 (NLRP3), which mediates the release of interleukin (IL)1β and IL18 (Fig.1). Fbxl2 protein itself is ubiquitinated and degraded by another protein, called Fbxo3. Inhibition of Fbxo3 results in increased Fbxl2 levels and decreased TRAF and NLRP3. Individuals with a natural occurring polymorphism within Fbxo3V221Ihave decreased lipopolysaccharide(LPS)-induced cytokine (TNFα, IL1β & IL6) production, Fbxo3 and TRAF levels and increased Fbxl2, providing human genetic target validation for Fbxo3-Fbxl2 axis modulation in inflammatory conditions. BC1261 is a first-in-class, selective, orally available Fbxo3 inhibitor in clinical development for the treatment of CD. Methods and Results In vitro data demonstrated that BC1261 binds to Fbxo3, prevents Fbxo3/Fbxl2 association and produces a concentration-dependent inhibition of LPS-induced release of TNFα and IL1β from human peripheral blood mononuclear cells. In an acute DSS-mouse model, administration of BC-1261 via drinking water ad libitum (30 μg/ml) or by daily intraperitoneal (IP) injection (150 μg) for 5 days resulted in the attenuation of the shortening of colonic length, tissue damage (Fig2.A), and TNFα and IL6 tissue levels (Fig.2B). In a repeated DSS-mouse model, BC-1261 (10 mg/kg bid) given orally for 19 days was comparable to the positive control (anti-p40) in the DAI composite (Fig2.C), stool consistency (Fig2.D), and histopathology score in the proximal colon (Fig2.E). BC-1261 also lead to clinically relevant reductions on endoscopy score (Fig2.F). Conclusion BC1261, a Fbxo3 inhibitor, was efficacious in both acute and chronic preclinical models of colitis. Taken together, these results suggest the potential utility of selective Fbxo3-Fbxl2 modulation in the treatment of CD.
27
Enika, Abazi. "Geopolitics in the Western Balkans: linkages, leverages and gatekeepers." Academicus International Scientific Journal 24 (July 2021): 85–108. http://dx.doi.org/10.7336/academicus.2021.24.06.
Full textAbstract:
With the end of the Cold War, Western Balkans countries have embraced the perspective of integration into the Euro-Atlantic structures, with the exception of Serbia and Bosnia-Herzegovina regarding accession in NATO. The return of international system from hegemonic to competitive followed by the ambiguities that accompany the integration into the Euro-Atlantic structures marked the return of competitors like China, Russia and Turkey in the regional affairs. To map out sources of influence and the context in which foreign interferences affect decision-making and interests, transfer ideas and norms in the region, the paper uses the concept of linkages that facilitate the understanding of opportunities and constrains, benefits and costs resulting from established relationship between Western Balkan countries and different international and regional powers. The paper makes a multi-level investigation of linkages developed between Western Balkans and the leverage of the most influential actors during the last decade, without undermining historical and societal context that favor of disfavor them.
28
Javorski, Elaine, and Liliane Brignol. "Journalists and Their Role in Selecting and Building News on Contemporary Transnational Migrations." Brazilian Journalism Research 13, no. 2 (2017): 28. http://dx.doi.org/10.25200/bjr.v13n2.2017.985.
Full textAbstract:
Over the last decade, Brazil has once more become a gateway for immigrants from different nations. This article presents a form for understanding the journalist’s role in selecting and building news on contemporary transnational migrations. In order to do this, a content analysis was made of excerpts from national and regional morning newscasts between 2014 and 2016 from Globo Network, Bom Dia Brasil and Bom Dia Paraná. The second stage of the investigation was a study of journalists from Paraná radio stations. This study consisted of a questionnaire and a focus group to help understand what kind of barriers journalists face when selecting news. The results show the limits for using personal experiences in news production and the social differences between journalists and sources; considered as an obstacle towards bringing minority issues and the dependence on bureaucratic sources to the forefront.O Brasil tornou-se, na última década, novamente a porta de entrada de imigrantes. É no sentido de compreender o papel do jornalista na seleção e construção da notícia sobre as migrações transnacionais contemporâneas que esse artigo se apresenta. Para tanto, foi realizada uma análise de conteúdo de peças encontradas nos telejornais matutinos de âmbito nacional e regional da TV Globo, Bom Dia Brasil e Bom Dia Paraná, entre 2014 e 2016. A segunda etapa da investigação consistiu em uma pesquisa com jornalistas de emissoras paranaenses por meio de questionários e da composição de um grupo focal na intenção de perceber, à luz da teoria do gatekeeping, quais as interferências sofridas pelos jornalistas na seleção das notícias. Os resultados apontam os limites da utilização das experiências pessoais na produção da notícia, as diferenças sociais entre jornalistas e fontes como empecilho para a visibilidade de assuntos referentes às minorias e a dependência das fontes burocráticas.El Brasil se ha convertido, en la última década, en una puerta de entrada de inmigrantes. Este artículo tiene como objetivo comprender el papel del periodista en la selección y construcción de la noticia sobre las migraciones transnacionales contemporáneas. Así, se llevó a cabo un análisis de contenido de piezas encontradas en los noticieros de la mañana en red nacional y regional de TV Globo, Bom Dia Brasil y Bom Dia Paraná, entre 2014 y 2016. La segunda etapa de la investigación consistió en una encuesta de periodistas de dos estaciones de Paraná a través de cuestionarios y la composición de un grupo de enfoque con el fin de entender, a partir de la teoría del gatekeeper, la interferencia sufrida por los periodistas en la selección de las noticias. Los resultados muestran los límites de la utilización de experiencias personales en la producción de noticias, las diferencias sociales entre periodistas y fuentes como impedimento para problemas de visibilidad relacionadas con las minorías y la dependencia de fuentes burocráticos.
29
Rinschen, Markus M., Pitter F. Huesgen, and Rachelle E. Koch. "The podocyte protease web: uncovering the gatekeepers of glomerular disease." American Journal of Physiology-Renal Physiology 315, no. 6 (2018): F1812—F1816. http://dx.doi.org/10.1152/ajprenal.00380.2018.
Full textAbstract:
Proteases regulate glomerular physiology. The last decade has revealed a multitude of podocyte proteases that govern the glomerular response to numerous chemical, mechanical, and metabolic cues. These proteases form a protein signaling web that integrates stress stimuli and serves as a key controller of the glomerular microenvironment. Both the extracellular and intracellular proteolytic networks are perturbed in focal segmental glomerulosclerosis, as well as hypertensive and diabetic nephropathy. Accordingly, the highly intertwined podocyte protease web is an integrative part of the podocyte’s damage response. Novel mass spectrometry-based technologies will help to untangle this proteolytic network: functional readouts acquired from deep podocyte proteomics, single glomerular proteomics, and degradomics have exposed unanticipated protease activity in podocytes. Future efforts should characterize the interdependency and upstream regulation of key proteases, along with their role in promoting tissue heterogeneity in glomerular diseases. These efforts will not only illuminate the machinery of podocyte proteostasis but also reveal avenues for therapeutic intervention in the podocyte protease web.
30
Wang, Jinping, and Lewen Wei. "Fear and Hope, Bitter and Sweet: Emotion Sharing of Cancer Community on Twitter." Social Media + Society 6, no. 1 (2020): 205630511989731. http://dx.doi.org/10.1177/2056305119897319.
Full textAbstract:
Emotions are non-negligible parts of the experience among the cancer-affected population to be reckoned with. With the increasing usage of social media platforms as venues for emotional disclosure, we ask the question, what and how are the emotions of the cancer community being shared there? Using a deep learning model and social network analysis, we investigated emotions expressed in a large collection of cancer-related tweets. The results showed that joy was the most commonly shared emotion, followed by sadness and fear, with anger, hope, and bittersweet being less shared. In addition, both the gatekeepers and influencers were more likely to post content with positive emotions, while gatekeepers refrained themselves from posting negative emotions to a greater extent. Last, cancer-related tweets with joy, sadness, and hope received more likes, whereas tweets with joy and anger were more retweeted. The implications of the findings are discussed in the context of social media health communities.
31
Kavelin, Chris. "Universities as the Gatekeepers of the Intellectual Property of Indigenous People's Medical Knowledge." Australian Journal of Indigenous Education 37, S1 (2008): 34–45. http://dx.doi.org/10.1375/s1326011100000351.
Full textAbstract:
AbstractThis paper will explore the role of universities as one of the most important gatekeepers that facilitate the appropriation of Indigenous medical knowledge (IMK) from Indigenous communities to transnational pharmaceutical corporations. The first section will deconstruct the “denial of dependency” upon IMK. Using case studies, the critique will demonstrate a complex mystification of Indigenous knowledge and labour, and a de-identification of Indigenous people and nature as the source of the medicines appropriated. The last section will analyse the law and policy context of the past 20 years that is responsible for creating a process of academic capitalism that has strengthened this phenomenon.
32
Cea, Michele, Antonia Cagnetta, Gabriella Cirmena, et al. "Hedgehog Signaling Is Useful as a Novel Molecular Marker for Predicting Relapse and Resistance During Chronic Myeloid Leukemia Treatment." Blood 116, no. 21 (2010): 1215. http://dx.doi.org/10.1182/blood.v116.21.1215.1215.
Full textAbstract:
Abstract Abstract 1215 Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a Leukemic Stem Cell (LSC) clone carrying a Philadelphia translocation, which outgrows the non-malignant haematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib, are the gold standard for CML treatment since each one shows an impressive rates of complete cytogenetic and molecular response in chronic phase (CP) CML. However the major problem concerning the final efficacy of TKIs therapy is that the majority of responding CP CML patients have detectable BCR-ABL transcripts which might arise from a population of quiescent CML LSC not effectively targeted by TKIs. Therefore the molecular monitoring not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Accordingly, it is necessary to monitor the appearance and increase of LSCs to identify and to treat quickly the fundamental responsible for relapse. Thus, we focused Hedgehog (Hh) signalling which has been proved essential for maintenance of cancer stem cells in myeloid leukaemia. Notably recent studies reported that the expansion of BCR-ABL positive leukemic stem cell is dependent on Hh pathway activation. Here, we analyzed the mRNA levels of Smoothened (SMO), a seven-transmembrane domain receptor protein, and Ptch1, a surface receptor regulator of SMO, in 20 CP-CML patients (8 High, 4 Intermediate and 8 Low Sokal Risk respectively) at diagnosis and during the follow-up. Using RT-PCR, in diagnosis setting, we proved that 60% of patients (bone marrow samples) showed Hh signalling significantly activated compared to CD34+ cells from healthy donors. In detail 75% (6/8) of High Sokal Risk CML patients showed an up-regulation of Smo and a down-regulation of Ptch1 mRNA levels, suggestive of active Hh signalling at diagnosis. Conversely Low and Intermediate Sokal Risk CML patients did not show features of Hh activation. Finally we monitored, during the follow-up, the mRNA levels of Smo and Ptch1 together with BCR-ABL to assess the kind of relationship between these parameters. Interestingly we noticed a direct correlation between the increase of BCR-ABL mRNA levels and signs of Hh activity (Smo mRNA increase level and Ptch1 mRNA decrease level). Characteristically, molecular monitoring highlighted that all patients developing resistance to TKIs treatment, showed a tendency to Hh activation (high and low mRNA levels of Patch1 and Smo respectively) few months before the development of Abl KD mutation (10/10). Typically this last behaviour was more evident in patients developing the gatekeeper mutation T315I. Finally, in accordance with published data, we noted that the pharmacological inhibition of Hh signalling impairs the growth of TKIs resistant human CML cell line BaF/T315I, suggesting a novel treatment option. All our data provide molecular evidence for a role of the stemness pathway to predict quickly both the relapse and the TKIs resistance during CML treatment. Therefore, we propose to use Ptch1 and Smo mRNA levels together with BCR-ABL for the molecular monitoring of CP CML. Disclosures: No relevant conflicts of interest to declare.
33
Steinberg, Donald. "Remarks by Donald Steinberg." Proceedings of the ASIL Annual Meeting 114 (2020): 235–38. http://dx.doi.org/10.1017/amp.2021.21.
Full textAbstract:
My work over the last forty-five years has been at the intersection of human rights, conflict transformation, and development with the U.S. government, civil society, and the United Nations. The clearest lesson I have learned is that peaceful, prosperous, and just societies only emerge when we draw on the leadership and contributions of all of society, including women, people with disabilities, racial and religious minorities, the LGBTQ community, displaced persons, and other marginalized groups. The paradox we face is that most of the policymakers and gatekeepers who are key to ensuring this diversity and inclusion are people like me: privileged, straight, older men with little direct experience of exclusion and abuse based on identity factors.
34
Guerci, Agnès, Emilie Cayssials, Philippe Rousselot, et al. "Interim Results of the Real-Life Study Evaluating the Efficacy and Safety of Ponatinib "Topase" Reveals Induction of Early Molecular Responses in Patients with TKI-Resistant or Intolerant CML." Blood 134, Supplement_1 (2019): 5908. http://dx.doi.org/10.1182/blood-2019-122769.
Full textAbstract:
Ponatinib is a third generation tyrosine kinase inhibitor (TKI) indicated in the treatment of CML-chronic phase (CP), accelerated phase (AP) and blast phase (BP) as well as in patients with the gatekeeper T315I mutation. TOPASE is the real life observatory initiated in France with the participation of 40 CML centers. We report here the interim results of the first 46 patients included in the study as of July 2019, which represents one of the largest real-life Ponatinib study to date in CML. Methods and Aims: CML Patients (Pts) > 18 years old, with any stage of disease treated with Ponatinib for a period of less than 6 months or prospectively, were included in the study since February 2018 (ambispective study). The principal aims were the evaluation of efficacy (haematological, cytogenetic and molecular responses), overall survival as well as the safety profile of the use of Ponatinib. After a period of 2 years of inclusion, 2 years of follow-up will be performed until 2022. The study will include 150 patients. Results: 48% of pts were female and 52% males and the median age was 57 +/-18 years. 87% of pts were in CP, 8.7% in AP and 4.3% in BP. The Sokal score was high (34.8% of Pts) intermediate (19.6% pts ) and low (28.3 % pts), not available in 17.4 %. The initiating dose was 15mg in 19 pts, 30mg in 16 pts and 45 mg in 11 pts. All patients with AP/BP except one, were treated with 45 mg/d. Previous therapies were 2 lines (44.4% of pts), 3 lines (26.7% pts), 1 line (17.8% of pts), 4 lines (6.7% of pts), and 5 lines (2.2% of pts) of TKI. The majority of pts had previously Dasatinib (77%) and Imatinib (70%) whereas 43% received Nilotinib and 31% Bosutinib. The last TKI administered prior to inclusion was Dasatinib (40.9% of pts) , Bosutinib (25% of pts) Nilotinib (18.2% of pts) , Imatinib (11.4% of pts) , Ponatinib (2.3% of pts) and ABL001 (2.3% of pts). There was no significant dose-initiation difference with regard to the previous TKI used. The main reason for the initiation of Ponatinib was failure and poor response to previous therapies (63% of pts) followed by intolerance (28.3% of pts). An ABL kinase mutation was detected in 11 patients during their TKI therapy. In 4 pts, the mutation was a T315I and in these pts the last TKI therapy was Nilotinib (n=2), Dasatinib ( n= 1) and Bosutinib ( n= 1). In 7 other patients, previous mutations detected were mostly in p-loop, with previous therapies including Dasatinib, Nilotinib, Imatinib and Bosutinib. One patient previously treated with Dasatinib, Nilotinib and Ponatinib (last therapy) had a F317L mutation, and two pts treated previously with 2 lines (Imatinib, Dasatinib) and 3 lines (Imatinib, Dasatinib, Nilotinib) had E255V/C1135 and F359C / E450K mutations, respectively. At the time of inclusion, the cardiovascular (CV) history of pts (n=46) included high blood pressure (HBP) (35% of pts) or other CV history (26.9%) including peripheral vascular disorders and ischemic heart disease. In the majority of pts with HBP, the initiating dose of Ponatinib was 15 mg/d ( 41%). Other significant medical disorders included diabetes ( 21.7% of pts ) and dyslipidemia ( 8.7% of pts). Results of the efficacy were evaluated at +3 Months (M3) and at +6 months (M6). M3 analyses were available on 18 pts (Figure 1) and M3+M6 analyses on 14 pts. At the entry of the study, the status of the 18 evaluable pts at M3 was as follows: no CHR (n=8), CHR (n=2), no CCyR ( n= 1) CCyR (n= 4), MMR (n=2), MR5 (n=1). At M3, CHR was obtained in 6/8 pts and 4 out of 6 attaining in the same time MMR and 1/6 reaching MR 4.5. For the remaining 10 pts, MMR was obtained in 5/10, and deep molecular responses in 4/10. At M6, out of 14 pts available for molecular analyses, 6 were in MMR, and 3 were in deep molecular responses. 3 pts had no response to Ponatinib. Analysis of responses in individual pts showed that in 8 pts unresponsive to previous therapies 2 had MMR and 1 MR 4. In 10 pts in CHR or absence of CyR, deep molecular responses were obtained in 5/10 pts. Overall, global improvement of responses was obtained in 55.6% at M3 and 60% in M6. At the time of the interim analysis no significant AE were noted for the 46 pts available for analysis. Conclusion: Ponatinib in real life situation is a highly efficient therapy in TKI-resistant and intolerant CML pts. Overall improvement was obtained in 60% of pts with early molecular responses, despite 2 or more previous TKI therapies in 70% of pts. The updated molecular results will be presented concerning M3, M6 and M9 timepoints. Funding : Incyte Biosciences, France Figure 1 Disclosures Guerci: INCYTE: Consultancy, Honoraria. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Huguet:Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Incyte Biosciences: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Berger:Incyte: Consultancy, Honoraria. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Turhan:novartis: Honoraria, Research Funding; Incyte: Consultancy, Honoraria.
35
Dillon, Matthew. "The Afterlives of the Archons: Gnostic Literalism and Embodied Paranoia in Twenty-First Century Conspiracy Theory." Gnosis: Journal of Gnostic Studies 5, no. 1 (2020): 71–96. http://dx.doi.org/10.1163/2451859x-12340077.
Full textAbstract:
Abstract This article analyzes the reception of the ancient Gnostic archons, or rulers, in contemporary conspiracy theories. In the classical Gnostic myth these nefarious beings rule the cosmos, mold primordial matter into a prison for Adam and Eve, and blind the Elect to their divine nature. These archons send cataclysms to earth and serve as celestial gatekeepers that keep the divine light trapped in their creation. Contemporary conspiracy theorists such as John Lamb Lash, David Icke, and Carol Reimer read the archons not as allegories or metaphors, but as real beings at work in contemporary politics, media and religion. Utilizing Michael Barkun’s concept of “superconspiracies,” this article examines how conspiracists Lash, Icke, and Reimer weave disparate conspiratorial discourses together through the classical Gnostic myth. The article concludes that the vast gulf between the anticosmic and anthropic dualism of the classical myth and the generally pro-cosmic and humanist thrust of modern esoterica leads these authors into paradoxical understands of cosmos, mind and eschatology.
36
Grondelaers, Stefan, and Roeland van Hout. "Is Standard Dutch with a regional accent standard or not? Evidence from native speakers' attitudes." Language Variation and Change 22, no. 2 (2010): 221–39. http://dx.doi.org/10.1017/s0954394510000086.
Full textAbstract:
AbstractThis paper reports a speaker evaluation experiment that investigated the competition between three regional accents of Standard Dutch and references to the speaker's profession as determinants of attitude formation. A stratified sample of listener-judges rated speech stimuli that were presented in two guises, a neutral guise and a teacher guise (the latter containing multiple references that revealed the speaker to be a high school teacher of Dutch). The experimental findings corroborate our earlier claim that regional flavoring is embedded in lay conceptualizations of Standard Dutch. Although teachers of Dutch may be the last “gatekeepers” of the standard in the Low Countries, they are not automatically downgraded when they have a regional accent: What matters is, clearly, which accent they have. Analysis of the ratings further suggests a hierarchical relation between accent and occupation as perception triggers: Even though regional accent clearly is the stronger attitude determinant, it does not suppress occupational information but interacts with it to generate richer social meaning.
37
Gruber, Daniel A. "Break Point: A Case Study of How Globalization and Technology Led to New Tennis Media Gatekeepers in the United States." International Journal of Sport Communication 7, no. 1 (2014): 126–41. http://dx.doi.org/10.1123/ijsc.2013-0135.
Full textAbstract:
This article presents a case study of the developments in media gatekeeping in the last 10 years, focusing on the launch of the Tennis Channel and the ascendance of ESPN as the major network for professional tennis in the United States. The U.S. broadcast networks NBC and CBS have ceded the exclusive television rights for 2 of the Grand Slam tournaments (Wimbledon, U.S. Open) to ESPN for the first time in over 40 years. Meanwhile, the Tennis Channel, despite its independence from the media conglomerates, has carved out a niche for fans with its extensive global coverage of tournaments and for advertisers with its lucrative audience demographics. This change in dominance after the broadcast networks reigned for over 4 decades underscores the globalization of the sport and the abundance of early-round tournament matches available to fans. Organizational theories are used to analyze what has occurred and to predict what will happen next for tennis media gatekeeping in the United States.
38
Turney, C. S. M., C. J. Fogwill, A. Klekociuk, et al. "Tropical and mid-latitude forcing of continental Antarctic temperatures." Cryosphere Discussions 9, no. 4 (2015): 4019–42. http://dx.doi.org/10.5194/tcd-9-4019-2015.
Full textAbstract:
Abstract. Future changes in atmospheric circulation and associated modes of variability are a major source of uncertainty in climate projections. Nowhere is this issue more acute than across the mid- to high-latitudes of the Southern Hemisphere (SH) which over the last few decades has experienced extreme and regional variable trends in precipitation, ocean circulation, and temperature, with major implications for Antarctic ice melt and surface mass balance. Unfortunately there is a relative dearth of observational data, limiting our understanding of the driving mechanism(s). Here we report a new 130-year annually-resolved record of δ D – a proxy for temperature – from the South Geographic Pole where we find a significant influence from extra-tropical pressure anomalies which act as "gatekeepers" to the meridional exchange of air masses. Reanalysis of global atmospheric circulation suggests these pressure anomalies play a considerably larger influence on mid- to high-latitude SH climate than hitherto believed, modulated by the tropical Pacific Ocean. Our findings suggest that future increasing tropical warmth will strengthen meridional circulation, exaggerating current trends, with potentially significant impacts on Antarctic surface mass balance.
39
Iype, Joseena, and Michaela Fux. "Basophils Orchestrating Eosinophils’ Chemotaxis and Function in Allergic Inflammation." Cells 10, no. 4 (2021): 895. http://dx.doi.org/10.3390/cells10040895.
Full textAbstract:
Eosinophils are well known to contribute significantly to Th2 immunity, such as allergic inflammations. Although basophils have often not been considered in the pathogenicity of allergic dermatitis and asthma, their role in Th2 immunity has become apparent in recent years. Eosinophils and basophils are present at sites of allergic inflammations. It is therefore reasonable to speculate that these two types of granulocytes interact in vivo. In various experimental allergy models, basophils and eosinophils appear to be closely linked by directly or indirectly influencing each other since they are responsive to similar cytokines and chemokines. Indeed, basophils are shown to be the gatekeepers that are capable of regulating eosinophil entry into inflammatory tissue sites through activation-induced interactions with endothelium. However, the direct evidence that eosinophils and basophils interact is still rarely described. Nevertheless, new findings on the regulation and function of eosinophils and basophils biology reported in the last 25 years have shed some light on their potential interaction. This review will focus on the current knowledge that basophils may regulate the biology of eosinophil in atopic dermatitis and allergic asthma.
40
Kimmitt, Abigail A. "Females as the Gatekeepers to Seasonal Breeding: What We Can Learn by Studying Reproductive Mechanisms in Both Sexes." Integrative and Comparative Biology 60, no. 3 (2020): 703–11. http://dx.doi.org/10.1093/icb/icaa095.
Full textAbstract:
Synopsis Seasonal reproduction is a widespread adaptation in vertebrates, such that individuals time their reproductive efforts to match peak resource abundance. Individuals rely on environmental cues to regulate hormonal mechanisms governing timing of breeding. Historically, studies on physiological mechanisms of seasonal reproduction, specifically in birds, have disproportionately focused on males compared to females. For this review, I conducted a literature search of the last decade of avian research and found a persistent sex bias in the field of physiological mechanisms of seasonal reproduction. Using work conducted with the dark-eyed junco (Junco hyemalis) as a case study, I present a possible solution to combat the sex bias: natural comparisons of populations that differ in reproductive timing to investigate mechanisms of reproduction in both sexes. Populations of dark-eyed juncos that differ in migratory behavior (i.e., migrant and resident) exhibit overlapping ranges during winter and early spring; residents begin breeding in early spring prior to the departure of migrants. This system, and others like it, provides an opportunity to compare mechanisms of reproduction in populations that differ in reproductive timing despite experiencing the same environmental conditions in early spring. In juncos, migrant and resident females and males exhibit similar patterns of hypothalamic regulation of reproduction in early spring, but sex differences in gonadal sensitivity between the populations could be an important distinction that partially explains sex differences in reproductive development. Comparing mechanisms of reproduction in free-living populations and in captivity can reveal important mechanisms that determine the onset of reproductive development, as well as potential sex differences in these mechanisms. Understanding the mechanisms of reproductive phenology has important implications for understanding how species will survive and reproduce in a changing climate.
41
Barker, Joel, and Chadrick Frederick. "Billions Lost Yearly To Earned Income Tax Credit: Errors Or Fraud?" Journal of Business & Economics Research (JBER) 14, no. 4 (2016): 145–52. http://dx.doi.org/10.19030/jber.v14i4.9803.
Full textAbstract:
The Earned Income Tax Credit is a refundable credit designed to assist working families with children; especially those who are considered to be living at or close to the poverty level. Over the last decade billions of dollars have been lost due to the improper application and fraudulent claims of the Earned Income Tax Credit (EITC). Critics believe that the program no longer serves its intended function because of the cumulative increase in the amounts lost each year; the legislation needs a major overhaul. The IRS have claimed that over 60 percent of the overpayments of EITC is due to manipulation of self-employed income and expenses, unqualified dependents being claimed, and misuse of single and head of household filing status. Even though the penalties for fraud and the lack of exercising due diligence are severe, these crimes continue to occur. While the tax authorities and other legislative bodies explore ways to combat these fraudulent claims, CPAs and other tax-preparers can assist in the fight against these crimes. As the de facto gatekeepers of the tax revenues, they are encouraged to exercise intensive due diligence and professional skepticism when claiming EITC for their clients.
42
Schiller, Devon. "The Face is (Not) Like a Mirror." International Journal of Semiotics and Visual Rhetoric 1, no. 2 (2017): 29–54. http://dx.doi.org/10.4018/ijsvr.2017070103.
Full textAbstract:
That ‘the face is like a mirror (to the soul)' resonates cross-culturally and trans-historically throughout the media imaginary of the last three millennia. But beyond its general habitual topos as an onto-cartographic blueprint in everyday life, the author presents this catoptric metaphor as a specific epistemological trope within the advertising designs that the author defines as face studies. Prospecting representative usages in the printed artifacts from scientific research, the author probes the print advertisements for scientific communications, newspaper cartoons, and periodical spreads–their intermedial and multimodal genealogies. The author then problematizes the metaphoric similitude between the face and a mirror as a fixedly stable type, with fluidly shifting tokens across explanatory models and pedagogical norms for the meaning of facial signs. Finally, the author proposes not only that scientific gatekeepers rhetorically diagrammatize semantic terms ‘face' and ‘mirror'–or other specular prostheses–in the brand identification and marketing narratives. It is with this method that they call for the attention of knowledge consumers, but also how these catoptric metaphors function as cognitive mechanisms to inspire conceptual and methodological innovation in science about the face itself.
43
Mohammed, Rebar Fatah, Ismail Aziz Asad, and Abduallah Al-Dabash. "The impact of inflation in the human levels of poverty and its impact on the performance of human capital In Iraq, for the period 2010- 2013." Journal of University of Human Development 2, no. 2 (2016): 45. http://dx.doi.org/10.21928/juhd.v2n2y2016.pp45-62.
Full textAbstract:
Demonstrates the concept of poverty to deny the poor access to basic basket of goods consisting of food, clothing and housing, in addition to a minimum of other needs, such as health care, transportation and education .and human capital in Iraq suffers from poverty capacity that qualify to contribute to economic development. Research has adopted a hypothesis: that inflation lowers the value of the currency and thus raise the poverty line, which contributes to the increase in the number of poor in the country, which contributes to reducing the skills and abilities of young people to contribute to economic development . The research aims to study the effect of inflation in increasing the number of poor people in Iraq through the study of the impact of inflation and its impact on the poverty line on human capital in Iraq. The research has come to conclusions which: : The poverty line in Iraq, equivalent to about $ 100 a month, less than the rate of $ 2 per day, and this means that Iraq's poor live in deprivation and extreme poverty compared to poor African countries, non-oil, which constitutes the poverty line, up to $ 30-60 per month. The reasons for the high rates of inflation in Iraq due to the absence of a clearly . The spread of financial and administrative corruption, according to a report in the governance of the international organization which ranked Iraq the last state in transparency. Some styles of gatekeepers and decision-makers to adopt Gatekeepers currency and pumped into the market or hard currency smuggling to neighboring countries . The research was presented proposals including: the development of macroeconomic policy include the ways and methods of reducing poverty in Iraq, and to benefit from the experiences of other countries such as Malaysia, Turkey and Singapore. Reduce the financial and administrative corruption through the dimensions of the corrupt and thieves for managerial positions and refer them to the courts . Open foreign direct investment in all areas of economic and service sectors to provide job opportunities contribute to the reduction of unemployment and poverty reduction.
44
Matloub, Yousif, Lia Gore, Mignon L. Loh, et al. "A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)." Blood 136, Supplement 1 (2020): 47. http://dx.doi.org/10.1182/blood-2020-134724.
Full textAbstract:
Introduction: Ph+ ALL accounts for 3-5% of pediatric ALL and is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) of 58-60% and 70-86%, respectively. Ponatinib is a potent third-generation TKI pan-BCR-ABL1 inhibitor that is active against BCR-ABL1 and all identified single resistance mutations, including the gatekeeper alteration, T315I, which confers resistance to other TKIs. Ponatinib has marketing approval in more than 50 countries, which includes the United States and European Union, for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. Ponatinib may also overcome drug resistance in pediatric patients with relapsed or resistant Ph+ ALL. This study will assess the pharmacokinetics, safety, and efficacy of ponatinib in pediatric patients. Methods: This Phase 1/2, single-arm, open-label, multicenter study (NCT04501614) will enroll approximately 18 patients in Phase 1 and 68 patients in Phase 2, including those enrolled in Phase 1 at the recommended Phase 2 dose (RP2D). Patients (aged ≥1 year to ≤21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with ABL class lesions will be enrolled. Enrolled patients must have either relapsed or are resistant or intolerant to ≥1 prior therapy with a BCR-ABL1-targeted TKI or have a BCR-ABL1 T315I mutation. Patients &gt;16 years must have a Karnofsky performance status ≥50%; patients ≤16 years must have a Lansky Play Scale ≥50%. During Phase 1, prior to availability of an age-appropriate formulation (AAF), patients must weigh ≥30 kg and be able to swallow tablets. The Phase 1 study will establish the RP2D of ponatinib in combination with the chemotherapy backbone using the adult tablet formulation in patients able to swallow tablets. Patients will receive fixed doses of ponatinib based on body weight ranges. The initially selected doses are expected to achieve systemic exposures that approximately match adult exposures after a 30-mg dose. Dose selection for the AAF will be in a separate cohort and informed by the results of a relative bioavailability study in healthy adult volunteers. A rolling 6 design will be used for both cohorts; additional cohorts may be enrolled at lower or higher doses based on the emerging data. In both Phase 1 and Phase 2, patients will receive two 35-day blocks of therapy (reinduction and consolidation). Each block includes 29 days of study treatment consisting of daily ponatinib and a modified United Kingdom ALL R3 chemotherapy backbone regimen, followed by a rest period of at least 6 days with daily ponatinib only. Disease assessment will occur at the end of each block. Patients will undergo an end-of-treatment visit 25 to 30 days after the last dose of study treatment in the consolidation block, or earlier if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. For the Phase 1 study, the primary endpoint is the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR-ABL1 domain mutations prior to and following ponatinib treatment. For the Phase 2 study, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints will be summarized descriptively, and include the proportion of patients in continued CR or who achieve CR at the end of consolidation, the proportion with minimal residual disease-negative status &lt;0.01% at the end of each block, and the proportion who relapsed or progressed, and time-to-event estimates including EFS, progression-free survival, and OS. The study will include approximately 70 study sites in approximately 16 countries. Disclosures Matloub: Takeda: Current Employment. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Pui:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Hanley:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Leonard:Takeda: Current Employment. Granier:Incyte: Current Employment. Silverman:Servier: Other: advisory board; Syndax: Other: advisory board; Takeda: Other: advisory board. OffLabel Disclosure: Ponatinib has marketing approval in the United States and European Union for adult patients with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. This trials-in-progress abstract describes a study in pediatric patients.
45
Turney, C. S. M., C. J. Fogwill, A. R. Klekociuk, et al. "Tropical and mid-latitude forcing of continental Antarctic temperatures." Cryosphere 9, no. 6 (2015): 2405–15. http://dx.doi.org/10.5194/tc-9-2405-2015.
Full textAbstract:
Abstract. Future changes in atmospheric circulation and associated modes of variability are a major source of uncertainty in climate projections. Nowhere is this issue more acute than across the mid-latitudes to high latitudes of the Southern Hemisphere (SH), which over the last few decades have experienced extreme and regionally variable trends in precipitation, ocean circulation and temperature, with major implications for Antarctic ice melt and surface mass balance. Unfortunately there is a relative dearth of observational data, limiting our understanding of the driving mechanism(s). Here we report a new 130-year annually resolved record of δD – a proxy for temperature – from the geographic South Pole where we find a significant influence from extratropical pressure anomalies which act as "gatekeepers" to the meridional exchange of air masses. Reanalysis of global atmospheric circulation suggests these pressure anomalies play a significant influence on mid- to high-latitude SH climate, modulated by the tropical Pacific Ocean. This work adds to a growing body of literature confirming the important roles of tropical and mid-latitude atmospheric circulation variability on Antarctic temperatures. Our findings suggest that future increasing tropical warmth will strengthen meridional circulation, exaggerating current trends, with potentially significant impacts on Antarctic surface mass balance.
46
Williams, Michele, Liuba Y. Belkin, and Chao C. Chen. "Cognitive Flexibility Matters: The Role of Multilevel Positive Affect and Cognitive Flexibility in Shaping Victims’ Cooperative and Uncooperative Behavioral Responses to Trust Violations." Group & Organization Management 45, no. 2 (2020): 181–218. http://dx.doi.org/10.1177/1059601120911224.
Full textAbstract:
Despite a significant growth in the scholarly literature in the area of trust violations and repair in the last decade, extant work has largely ignored the complex and socially competent responses of the victims of these violations. Our framework integrates insights from affective events theory, the broaden-and-build theory of positive emotions, and theories of cognitive processing to suggest that cognitive flexibility is central to understanding how individuals respond to trust violations. Rather than viewing victims solely as gatekeepers to trust repair, we examine how victims’ cognitive processes are influenced by the affective context of those violations, which can, in turn, produce a spectrum of nuanced behavioral responses. We refer to this spectrum as the “swollen middle,” the range of behavior that resides between the extremes of impulsive revenge and forgiveness-based, communal cooperation. By integrating psychological theories of emotion and cognitive processing, we seek to highlight the central role of cognitive flexibility in the range of cooperative responses to trust violations. More broadly, we seek to contribute to the emergence of a new paradigm for studying interpersonal trust at work—a paradigm that explores trust-violating events as situated affect-laden experiences that interact with relevant organizational and interpersonal factors to influence employee behavior and trust dynamics in organizations.
47
Okumu, Willis, Kaderi Noagah Bukari, Papa Sow, and Evans Onyiego. "The role of elite rivalry and ethnic politics in livestock raids in northern Kenya." Journal of Modern African Studies 55, no. 3 (2017): 479–509. http://dx.doi.org/10.1017/s0022278x17000118.
Full textAbstract:
ABSTRACTThis paper argues that livestock raids and pastoralists’ competition over water and pastures in north-western Kenya are manifestations of local ethnic political contests and rivalries. The culture of raiding among the Samburu, Turkana, Pokot, Borana, Gabra and Rendille communities has changed over the last 40 years. Whereas elders were once the gatekeepers of communal institutions, today new actors are at the forefront of new forms of violent raids. Among Samburu and Turkana communities, politicians and shrewd businessmen have emerged to exploit ethnic rivalry that exists between these groups and use it to mobilise raids. These political and business elites play influencing roles in raiding by paying and arming warriors to carry out raids. Competition for political influence is closely intertwined with competition over scarce water resources and grazing pastures among Turkana and Samburu. Given that pastoralists survive on decreasing pasture and water resources, our study shows that political elites arm their communities during the dry season to gain the upper hand in contests over access to limited resources. Livestock raids no longer occur in the traditional context of restocking, but rather as an expression and manifestation of local ethnic politics and political contests between ethnic kingpins. The study uses primary field data from a case study collected through in-depth interviews, oral history and group discussions with various actors.
48
Bestor, Nick. "Making and remaking the Galaxy Far, Far Away." Science Fiction Film & Television: Volume 14, Issue 2 14, no. 2 (2021): 145–68. http://dx.doi.org/10.3828/sfftv.2021.11.
Full textAbstract:
This article examines West End Games’ Star Wars: The Roleplaying Game, first published in 1987, and its foundational role in the worldbuilding process of the Star Wars franchise (1977-). In producing the game, West End Games contributed significantly to defining and organizing the storyworld, refining and expanding the scope of Star Wars by integrating some earlier transmedial extensions while excluding others. Coming at an early point in the franchise’s history, before Lucasfilm exerted as much control over its licensees, The Roleplaying Game offers an opportunity to examine the role that licensed game designers can play as architects and gatekeepers of transmedia worldbuilding, codifying what is and is not remembered within the storyworld. The Roleplaying Game has often been reduced to a footnote in both the popular and academic history of Star Wars transmedia, but beyond adapting the Galaxy Far, Far Away to a setting for imaginative tabletop roleplaying, The Roleplaying Game is also a foundational document for the last three decades of the Star Wars franchise, serving as the early ‘story bible’ for the Expanded Universe, the interconnected network of Star Wars paratexts codified by the licensing department of Lucasfilm during the 1990s. The hundreds of Star Wars novels, comics, games and other transmedia productions that came with the franchise’s dramatic rebirth in the 1990s bear the stamp of the worldbuilding labour of West End Games.
49
Pinilla, Leonor, Enrique Aguilar, Carlos Dieguez, Robert P. Millar, and Manuel Tena-Sempere. "Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms." Physiological Reviews 92, no. 3 (2012): 1235–316. http://dx.doi.org/10.1152/physrev.00037.2010.
Full textAbstract:
Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.
50
Langley, Paul. "Medicaid Formulary Decisions and the Institute for Clinical and Economic Review: Abandoning Pseudoscience in Imaginary Pharmaceutical Pricing Claims." INNOVATIONS in pharmacy 12, no. 1 (2021): 11. http://dx.doi.org/10.24926/iip.v12i1.3702.
Full textAbstract:
Medicaid formulary committees and other gatekeepers face a difficult task. On the one hand they can utilize technical expertise in evaluating the real world evidence for clinical, quality of life and resource utilization claims for competing products while on the other hand they may be asked to assess claims built by simulation models for pricing and product access. A common option has been to take modeled claims from third parties such as the Institute for Clinical and Economic Review (ICER) at face value without challenging the model structure, its assumptions and its incremental cost-per-QALY claims set against competing products or the existing standard of care. Unfortunately, from the available evidence, it seems clear that many formulary assessment groups, last but not least those for whom the ICER modeling claims are targeted, have little if any appreciation of the limitations of ICER modeling. There are two substantive issues: (i) a failure to appreciate the limitations imposed by the standards of normal science for credible, empirically evaluable and replicable product claims and (ii) an understanding of limitations imposed by the axioms of fundamental measurement. In the latter case, a failure to recognize that the quality adjusted life year (QALY) is an impossible mathematical construct (hence the I-QALY). To these limitations should be added the potential for constructing competing imaginary claims. Surprisingly, ICER has provided the ideal opportunity to construct competing claims with the launch in late 2020 of the ICER Analytics cloud platform. Formulary committees and other health decision makers should be aware that claims based on the ICER Analytics platform together with competing lifetime modelled claims all fail the standards of normal science. Factoring these into formulary decisions is not only misguided but may have unintended consequences for pricing and access that may disadvantage significantly patients and caregivers. We have spent too much time debating the merits or otherwise of the I-QALY for targeted patient groups with the parties failing to recognize that the focus on simulated cost-per-I-QALY value assessments is a mathematical folly; I-QALY claims are a chimera. The I-QALY, at long last, should be abandoned together with modelled lifetime simulations. Medicaid formulary decision makes should rethink the required evidence base for formulary decisions and negotiations. Care should be taken to revisit previous negotiations where ICER recommendations have been utilized to support pricing and access.