PURPOSE: RNA interference mediated by small interfering RNAs (siRNAs) is a powerful technology allowing the silencing of mamalian genes with great specificity and potency. The purpose of this study was to demonstrate the feasibility of RNA interference mediated by siRNA in retinal cells in vitro and in the murine retina in vivo. METHODS: siRNAs specific for enhanced green fluorescent protein (EGFP) and murine and human vascular endothelial growth factor (VEGF) were designed. In vitro studies in human cell lines entailed modulation of endogenous VEGF levels through chemically induced hypoxia. Effects of siRNA treatment on these levels were measured by ELISA. In vivo studies evaluating effects of siRNA on levels of EGFP and VEGF were performed by co-injecting recombinant viruses carrying EGFP or hVEGF cDNAs along with the appropriate siRNAs subretinally in mice. Additional studies aimed at blocking production of endogenous mVEGF were performed using laser-induced choroidal neovascularization (CNV) in mice. Effects of in vivo treatments were evaluated ophthalmoscopically. Retinal/choroidal flat mounts were evaluated after perfusion with dextran-fluorescein. Alternatively, retinas were evaluated in histological sections or VEGF levels were measured in intact eyes using ELISA. RESULTS: Successful delivery of siRNA to the subretinal space was confirmed by observing significantly reduced levels of EGFP in eyes treated with Ad.CMV.EGFP plus EGFP-directed siRNA. siRNAs directed against hVEGF effectively and specifically inhibit hypoxia-induced VEGF levels in human cell lines and after adenoviral induced hVEGF transgene expression in vivo. In addition, subretinal delivery of siRNA directed against murine Vegf significantly inhibited CNV after laser photocoagulation. CONCLUSIONS: Delivery of siRNA can be used in vitro and in vivo to target specific RNAs and to reduce the levels of the specific protein product in the targeted cells. This work suggests that RNA interference has potential for application to studies of retinal biology and for the treatment of a variety of retinal diseases, including those involving abnormal blood vessel growth.
B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
This paper offers and tests an approach to conceptualizing the global competency of engineers. It begins by showing that the often-stated goal of working effectively with different cultures is fundamentally about learning to work effectively with people who define problems differently. The paper offers a minimum learning criterion for global competency and three learning outcomes whose achievement can help engineering students fulfill that criterion. It uses the criterion to establish a typology of established methods to support global learning for engineering students. It introduces the course, Engineering Cultures, as an example of an integrated classroom experience designed to enable larger numbers of engineering students to take the critical first step toward global competency, and it offers a test application of the learning criterion and outcomes by using them to organize summative assessments of student learning in the course.
We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline (DPD) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group (chi2 = 10.935; p = 0.0273). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were -1.8 +/- 0.6%, -2.4 +/- 0.7%, and -3.3 +/- 0.8% for the control group, and 1.4 +/- 0.7%, -0.1 +/- 0.6%, and -0.5 +/- 1.0% for the vitamin K2-treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group (p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 +/- 0.3 ng/ml and 1.6 +/- 0.1 ng/ml, respectively (p < 0.0001), while the serum level of OC measured by the conventional radioimmunoassay (RIA) showed a significant rise (42.4 +/-6.9% from the basal value) in the treated group at 24 months (18.2 +/- 6.1% for the controls;p = 0.0081). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule.
SUMMARY Science and technology are embedded in virtually every aspect of modern life. As a result, people face an increasing need to integrate information from science with their personal values and other considerations as they make important life decisions about vaccinating their children and other medical care, the safety of foods, what to do about climate change, and many other issues. Communicating science effectively, however, is a complex task and an acquired skill. Moreover, the approaches to communicating science that will be most effective for specific audiences and circumstances often are not obvious. Fortunately, an expanding science base from diverse disciplines can support science communicators in making these determinations. The purpose of this report is to offer a research agenda for science communicators and researchers seeking to apply this research and fill gaps in knowledge about how to communicate effectively about science, with a particular focus on issues that are contentious in the public sphere. Examples include climate change, stem cells, nanotechnology, vaccines, hydraulic fracturing, genetically modified organisms, nuclear energy, obesity, education policy, and the teaching of evolution and climate change in K-12 schools. To inform the research agenda, the study committee sought to identify important influences—psychological, economic, political, social, cultural, and mediarelated—on how science associated with such issues is understood, perceived, and used. For the purposes of this report, “science communication” is defined as the exchange of information and viewpoints about science to achieve a goal or objective such as fostering greater understanding of science and scientific methods or gaining greater insight into diverse public views and concerns about the science related to a contentious issue.
This article proposes a general explanation for social background‐related inequality. Educational attainment research indicates that the later an education transition, the lower the social background effect. While some suggest life course changes in the parent‐child relationship or between‐family competition explain this pattern, others contend the result is a statistical artifact, and that the analytic strategy presupposes agents are irrationally myopic. This article addresses these criticisms by framing educational transitions in terms of students' movement through the stratified curriculum. Students select their stratum, one of which is dropping out. To make these choices, they consider their most recent salient performance. Using time‐varying performance measures to predict students' track placement/school continuation sustains the validity of the educational transitions approach and suggests substantively important social background effects even for nearly universal transitions. Results are consistent with the general perspective termed effectively maintained inequality.
In December 2019, a novel pneumonia caused by a previously \nunknown pathogen emerged in Wuhan, a city of 11 million \npeople in central China. The initial cases were linked to \nexposures in a seafood market in Wuhan.1 As of January 27, \n2020, the Chinese authorities reported 2835 confirmed cases in \nmainland China, including 81 deaths. Additionally, 19 confirmed \ncases were identified in Hong Kong, Macao and Taiwan, and 39 \nimported cases were identified in Thailand, Japan, South Korea, \nUnited States, Vietnam, Singapore, Nepal, France, Australia \nand Canada. The pathogen was soon identified as a novel \ncoronavirus (2019-nCoV), which is closely related to sever acute \nrespiratory syndrome CoV (SARS-CoV).2 Currently, there is no \nspecific treatment against the new virus. Therefore, identifying \neffective antiviral agents to combat the disease is urgently \nneeded.
Biochar (BC) produced from agricultural crop residues has proven effective in sorbing organic contaminants. This study evaluated the ability of dairy-manure derived biochar to sorb heavy metal Pb and organic contaminant atrazine. Two biochar samples were prepared by heating dairy manure at low temperature of 200 degrees C (BC200) and 350 degrees C (BC350). The untreated manure (BC25) and a commercial activated C (AC) were included as controls. Sorption of Pb by biochar followed a dual Langmuir-Langmuir model, attributing to Pb precipitation (84-87%) and surface sorption (13-16%). Chemical speciation, X-ray diffraction, and infrared spectroscopy indicated that Pb was precipitated as beta-Pb9(PO4)6 in BC25 and BC200 treatment, and as Pb3(CO3)2(OH)2 in BC350. Lead sorption by AC obeyed a single Langmuir model, attributing mainly to surface sorption probably via coordination of Pb d-electron to C==C (pi-electron) and --0--Pb bonds. The biochar was 6 times more effective in Pb sorption than AC, with BC200 being the most effective (up to 680 mmol Pb kg(-1)). The biochar also effectively sorbed atrazine where atrazine was partitioned into its organic phase, whereas atrazine uptake by AC occurred via surface sorption. When Pb and atrazine coexisted, little competition occurred between the two for sorption on biochar, while strong competition was observed on AC. Results from this study indicated that dairy manure can be converted into value-added biochar as effective sorbent for metal and/or organic contaminants.
Incorporation of dioleoyl N-(monomethoxy polyethyleneglycol succinyl)phosphatidylethanolamine (PEG-PE) into large unilamellar liposomes composed of egg phosphatidylcholine:cholesterol (1:1) does not significantly increase the content leakage when the liposomes are exposed to 90% human serum at 37 degrees C, yet the liposomes show a significant increase in the blood circulation half-life (t1/2 = 5 h) as compared to those without PEG-PE(t1/2 less than 30 min). The PEG-PE's activity to prolong the circulation time of liposomes is greater than that of the ganglioside GM1, a well-described glycolipid with this activity. Another amphipathic PEG derivative, PEG stearate, also prolongs the liposome circulation time, although its activity is less than that of GM1. Amphipathic PEGs may be useful for the sustained release and the targeted drug delivery by liposomes.
With the rapid increase of large-scale datasets, biomedical data visualization is facing challenges. The data may be large, have different orders of magnitude, contain extreme values, and the data distribution is not clear. Here we present an R package ggbreak that allows users to create broken axes using ggplot2 syntax. It can effectively use the plotting area to deal with large datasets (especially for long sequential data), data with different magnitudes, and contain outliers. The ggbreak package increases the available visual space for a better presentation of the data and detailed annotation, thus improves our ability to interpret the data. The ggbreak package is fully compatible with ggplot2 and it is easy to superpose additional layers and applies scale and theme to adjust the plot using the ggplot2 syntax. The ggbreak package is open-source software released under the Artistic-2.0 license, and it is freely available on CRAN ( https://CRAN.R-project.org/package=ggbreak ) and Github ( https://github.com/YuLab-SMU/ggbreak ).
Original article can be found at: http://www.iop.org/EJ/journal/aj Copyright American Astronomical Society DOI: 10.1088/0004-6256/136/6/2782 [Full text of this article is not available in the UHRA]
BACKGROUND/AIMS: Platelets are critically important for primary haemostasis and the major players in thrombotic vascular occlusion. Platelets are activated by agonists, such as thrombin and collagen-related peptide as well as second-wave mediators including thromboxane A2 via different intracellular signaling pathways resulting in degranulation, aggregation and thrombus formation. Platelet activation is paralleled by phosphorylation and activation of p38 MAPK. The limited specificity of hitherto known p38 MAPK inhibitors precluded safe conclusions on the precise role of p38 MAPK in the regulation of platelet function. The present study examined the impact of Skepinone-L, a novel and highly selective inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), on platelet activation and thrombus formation. METHODS: Experiments were performed in freshly isolated human platelets. Protein phosphorylation was quantified by Western blotting, thromboxane B2 synthesis by enzyme immunoassay, ATP release by ChronoLume luciferin assay, cytosolic Ca(2+) concentration by Fura-2 fluorescence-measurements, platelet aggregation by a light transmissions measurement and in vitro thrombus formation by a flow chamber. RESULTS: Skepinone-L (1 μM) virtually abrogated the phosphorylation of platelet p38 MAPK substrate Hsp27 following stimulation with CRP (1 μg/ml), thrombin (5 mU/ml) or thromboxane A2 analogue U-46619 (1 μM). Furthermore, Skepinone-L significantly blunted activation-dependent platelet secretion and aggregation following threshold concentrations of CRP, thrombin and thromboxane A2 analogue U-46619. Skepinone-L did not impair platelet Ca(2+) signaling but prevented agonist-induced thromboxane A2 synthesis through abrogation of p38 MAPK-dependent phosphorylation of platelet cytosolic phospholipase A2 (cPLA2). Skepinone-L further markedly blunted thrombus formation under low (500-s) and high (1700-s) arterial shear rates. CONCLUSIONS: The present study discloses a powerful inhibiting effect of p38 MAPK-blocker Skepinone-L on platelet activation and thrombus formation.
PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. CONCLUSION: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
Abstract Human–wildlife conflict is one of the most critical threats facing many wildlife species today, and the topic is receiving increasing attention from conservation biologists. Direct wildlife damage is commonly cited as the main driver of conflict, and many tools exist for reducing such damage. However, significant conflict often remains even after damage has been reduced, suggesting that conflict requires novel, comprehensive approaches for long‐term resolution. Although most mitigation studies investigate only the technical aspects of conflict reduction, peoples' attitudes towards wildlife are complex, with social factors as diverse as religious affiliation, ethnicity and cultural beliefs all shaping conflict intensity. Moreover, human–wildlife conflicts are often manifestations of underlying human–human conflicts, such as between authorities and local people, or between people of different cultural backgrounds. Despite evidence that social factors can be more important in driving conflict than wildlife damage incurred, they are often ignored in conflict studies. Developing a broader awareness of conflict drivers will advance understanding of the patterns and underlying processes behind this critical conservation issue. In this paper, I review a wide variety of case studies to show how social factors strongly influence perceptions of human–wildlife conflict, and highlight how mitigation approaches should become increasingly innovative and interdisciplinary in order to enable people to move from conflict towards coexistence.
In this volume, Ting-Toomey and Oetzel accomplish two objectives: to explain the culture-based situational conflict model, including the relationship among conflict, ethnicity, and culture; and, second, integrate theory and practice in the discussion of interpersonal conflict in culture, ethnic, and gender contexts. While the book is theoretically directed, it is also a down-to-earth practical book that contains ample examples, conflict dialogues, and critical incidents. Managing Intercultural Conflict Effectively helps to illustrate the complexity of intercultural conflict interactions and readers will gain a broad yet integrative perspective in assessing intercultural conflict situations. The book is a multidisciplinary text that draws from the research work of a variety of disciplines such as cross-cultural psychology, social psychology, sociology, marital and family studies, international management, and communication.
Developing the capacity for individuals to learn effectively from their experiences is an important part of building the knowledge and skills in organizations to do good adaptive management. This paper reviews some of the research from cognitive psychology and phenomenography to present a way of thinking about learning to assist individuals to make better use of their personal experiences to develop understanding of environmental systems. We suggest that adaptive expertise (an individual's ability to deal flexibly with new situations) is particularly relevant for environmental researchers and practitioners. To develop adaptive expertise, individuals need to: (1) vary and reflect on their experiences and become adept at seeking out and taking different perspectives; and (2) become proficient at making balanced judgements about how or if an experience will change their current perspective or working representation of a social, economic, and biophysical system by applying principles of "good thinking." Such principles include those that assist individuals to be open to the possibility of changing their current way of thinking (e.g., the disposition to be adventurous) and those that reduce the likelihood of making erroneous interpretations (e. g., the disposition to be intellectually careful). An example of applying some of the principles to assist individuals develop their understanding of a dynamically complex wetland system (the Macquarie Marshes in Australia) is provided. The broader implications of individual learning are also discussed in relation to organizational learning, the role of experiential knowledge for conservation, and for achieving greater awareness of the need for ecologically sustainable activity.
ADVERTISEMENT RETURN TO ISSUEEditorialNEXTHow to Effectively Utilize MOFs for ElectrocatalysisSong Jin*Song JinDepartment of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States*E-mail: [email protected]More by Song Jinhttp://orcid.org/0000-0001-8693-7010Cite this: ACS Energy Lett. 2019, 4, 6, 1443–1445Publication Date (Web):June 14, 2019Publication History Published online14 June 2019Published inissue 14 June 2019https://pubs.acs.org/doi/10.1021/acsenergylett.9b01134https://doi.org/10.1021/acsenergylett.9b01134editorialACS PublicationsCopyright © 2019 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views10878Altmetric-Citations126LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (437 KB) Get e-AlertscloseSUBJECTS:Catalysts,Materials,Metal organic frameworks,Metals,Radiology Get e-Alerts
A pplied research organizations invest a great deal of time, and research funders invest a great deal of money generating and (one hopes) transferring research knowledge that could inform decisions about health and health care. Basing these knowledge‐transfer activities on our evolving understanding of the most effective approaches to knowledge transfer will help us achieve value for money in our individual and collective investments in health services and health policy research. Research organizations and research funders can probably be excused for not basing their activities on research evidence until now, however, because the variety of relevant questions, target audiences, and disciplinary perspectives and methodological approaches used in empirical studies has made the identification of take‐home messages from this field of research a very difficult task. We provide an organizing framework for a knowledge‐transfer strategy and an overview of our understanding of the current knowledge for each of the five elements of the framework. The framework provides an overall approach to knowledge transfer that can be evaluated as a whole over long periods of time, as well as specific elements that can be evaluated and fine‐tuned over shorter periods of time.
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We construct a class of lattice systems that have effectively nonintegral dimensionality. A reasonable definition of effective dimensionality applicable to lattice systems is proposed and the effective dimensionalities of these lattices are determined. The renormalization procedure is used to determine the critical behavior of the classical XY model and the Fortuin–Kasteleyn cluster model on the truncated tetrahedron lattice which is shown to have the effective dimensionality 2 log3 /log5. It is found that no phase transition occurs at any finite temperature.