Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs

Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases

So You Need a Water Well? A Consumer\u27s Guide to Homeowners\u27 Drinking Water

Le magazine d'information Savoir(s) de l'Université de Strasbourg du mois de mai 2014 portait sur la propriété intellectuelle et la production / circulation de la connaissance. Il est disponible en ligne (pdf

TEM10 homodyne detection as an optimal small displacement and tilt measurements scheme

We report an experimental demonstration of optimal measurements of small displacement and tilt of a Gaussian beam - two conjugate variables - involving a homodyne detection with a TEM10 local oscillator. We verify that the standard split detection is only 64% efficient. We also show a displacement measurement beyond the quantum noise limit, using a squeezed vacuum TEM10 mode within the input beam.Comment: 9 pages, 8 figure

A comparison of optical and radar measurements of mesospheric winds and tides

Optical measurements of mesospheric winds by Fabry‐Perot spectrometers, FPSs, at Mawson, 67.6°S 62.9°E, and Davis, 68.6°S 78.0°E, Antarctica are compared with similar measurements obtained using a spaced‐antenna MF radar at Davis. The FPSs observed the OH emission. Different analysis procedures, used to determine the mean wind, and amplitude and phase of the semidiurnal tide, have been compared. At these latitudes the diurnal tide is weak and the semi‐diurnal tide, although highly variable in amplitude, is usually the dominant periodicity. When comparing the amplitude and phase of the semidiurnal tide good agreement is obtained between measurements by the two instruments

Strategic Alliances In The Financial Services And Chemical Industries

The penetration and practice of strategic alliances and Total Quality Management in a goods industry (Chemical Industry) was compared to that for a service industry (Financial Services).   The ingoing hypothesis that the Financial Services Industry and the Chemical Industry were similar as it relates to strategic alliances and TQM, based on the longevity of these concepts, was not fully supported. Clear industry similarities and differences were noted. For example, the penetration of TQM and strategic alliances was deeper in the Chemical Industry. This is thought to be the result of the earlier application of TQM and strategic alliances in goods industries. Company size, as measured by revenue, did not affect whether small or medium sized companies in either industry practiced TQM, engaged in strategic alliances or the number of strategic alliances that each had.  The proportion of strategic alliance practitioners who also practiced TQM was statistically similar for both industries. Importantly, a high, and similar, proportion of strategic alliance participants in both industries achieved business growth.  While those practitioners did achieve a reduction of the numbers of suppliers there is significant room for improvement in both industries. Strategic alliance performance met or exceeded expectations and alliance costs were on or below forecasts in both industries but the result was significantly better for the Financial Services industry in both instances. The lower outcomes for the Chemical Industry are most likely rooted in negative aspects of relationships with strategic alliance partners as suggested by the top 5 advantages and top 5 disadvantages responses. Significantly, a high proportion of strategic alliances will continue with most of these being with the current partner and a few with new partners.  The Financial Services Industry outperforms the Chemical Industry on this measure.It is recommended that firms in the Financial Services Industry closely examine the benefits that strategic alliances can yield, and then conduct pilot tests. On the other hand, firms in the Chemical Industry need to improve their relationships with potential partners in order to maximize the outcome of strategic alliances

Strategic Alliances In The Food And Beverage Industry

Strategic Alliances are an important component of an effective Total Quality Management program (TQM) and of business growth.  The Food and Beverage industry was studied as part of a long-term longitudinal research program, covering diverse industries, to determine the extent of penetration and effectiveness of strategic alliances and TQM. The results indicated that 62% of respondents participate in strategic alliances and 82% practice TQM. Over 74% of firms that did participate reported achieving or exceeded alliance goals and, significantly, 73% experienced increased business revenue. Approximately 11.84% of participants reported that costs exceeded expectations while 15.13% enjoyed lower costs. Some methods to enhance strategic alliance effectiveness are discussed. Total Quality Management (TQM) is a philosophy that includes the idea that to achieve the highest level of quality one must extend the quality system and program as far back in the Supply Chain as possible, i.e., to the supplier(s), the supplier’s supplier and beyond if applicable (first, second, third, etc., tier suppliers), and as far forward as possible, i.e., to customers1.  TQM also embraces the following five concepts namely; continuous improvement  (a never ending search for perfection), bench-marking (learning from the “best-of-the best or “best-in-class”), use of empowered employee teams6, just-in-time practices (JIT) (use of strategic alliances and few suppliers2), and knowledge of tools (at least 51 tools including Statistical Quality Control3). JIT practices include the use of strategic alliances; which may be with first, second and third tier suppliers and/or with customers; to achieve competitive advantages as well as to improve quality throughout the business system of an enterprise.2   A Strategic Alliance is a formal agreement to supply a good(s) or services(s) and to jointly expand knowledge, develop applications and commercialize new products, with the rights of co-ownership, and commercial exploitation of the inventions within the boundaries of the Alliance particulars. Alliance partners work together to serve the ultimate consumer by doing together what each partner could not do alone. The Strategic Alliance agreement includes Supply, Technology, Intellectual Property, Legal and Termination/Disengagement sub-agreements and, generally, has a term of at least 3 years but not usually more than 5 years. The objective of a Strategic Alliance is to achieve competitive advantage for each partner through productivity and quality improvements and significant innovation.2 This research was undertaken to determine the penetration of TQM and strategic alliances in the Food and Beverage industry.  The intent is to re-study this industry in about 4 to 5 years to understand the evolution of TQM and strategic alliances from the baseline reported herein. The authors comprise the Strategic Alliance Research Group that expects to study a broad array of US industries on these subjects.5 The reader is referred to the authors’ Web site at www.tsarg.com for the organization’s vision, mission, objectives and recent research

How To Implement Online Surveying And A Comparison With Traditional Surveys

This paper is divided into two parts.  The first part will discuss the techniques needed to implement a web-based survey.  Part two will present the results that the authors have obtained using web-based surveying verses the traditional return by mail/fax surveys. A number of issues need to be addressed before a web-based survey can be implemented.  Those issues are: selection of an Internet Service Provider, selection of server software, selection of Web creation software, building the web site, creating the form, and linking the website to a database.  The authors have conducted five major surveys over the last three years.  The last three surveys have given the respondents the option of filling out the survey and mailing/faxing it back or responding online.  The results reveal a bias against the web.  We will discuss some of the reasons we believe this to be the case

Cyclic Di-GMP Riboswitch-Regulated Type IV Pili Contribute to Aggregation of Clostridium difficile

Clostridium difficile is an anaerobic Gram-positive bacterium that causes intestinal infections with symptoms ranging from mild diarrhea to fulminant colitis. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that typically regulates the switch from motile, free-living to sessile and multicellular behaviors in Gram-negative bacteria. Increased intracel- lular c-di-GMP concentration in C. difficile was recently shown to reduce flagellar motility and to increase cell aggregation. In this work, we investigated the role of the primary type IV pilus (T4P) locus in c-di-GMP-dependent cell aggregation. Inactivation of two T4P genes, pilA1 (CD3513) and pilB1 (CD3512), abolished pilus formation and significantly reduced cell aggregation un- der high c-di-GMP conditions. pilA1 is preceded by a putative c-di-GMP riboswitch, predicted to be transcriptionally active upon c-di-GMP binding. Consistent with our prediction, high intracellular c-di-GMP concentration increased transcript levels of T4P genes. In addition, single-round in vitro transcription assays confirmed that transcription downstream of the predicted transcription terminator was dose dependent and specific to c-di-GMP binding to the riboswitch aptamer. These results support a model in which T4P gene transcription is upregulated by c-di-GMP as a result of its binding to an upstream transcriptionally activating riboswitch, promoting cell aggregation in C. difficile.Clostridium difficile is an anaerobic Gram-positive bacterium that causes intestinal infections with symptoms ranging from mild diarrhea to fulminant colitis. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that typically regulates the switch from motile, free-living to sessile and multicellular behaviors in Gram-negative bacteria. Increased intracellular c-di-GMP concentration in C. difficile was recently shown to reduce flagellar motility and to increase cell aggregation. In this work, we investigated the role of the primary type IV pilus (T4P) locus in c-di-GMP-dependent cell aggregation. Inactivation of two T4P genes, pilA1 (CD3513) and pilB1 (CD3512), abolished pilus formation and significantly reduced cell aggregation un- der high c-di-GMP conditions. pilA1 is preceded by a putative c-di-GMP riboswitch, predicted to be transcriptionally active upon c-di-GMP binding. Consistent with our prediction, high intracellular c-di-GMP concentration increased transcript levels of T4P genes. In addition, single-round in vitro transcription assays confirmed that transcription downstream of the predicted transcription terminator was dose dependent and specific to c-di-GMP binding to the riboswitch aptamer. These results support a model in which T4P gene transcription is upregulated by c-di-GMP as a result of its binding to an upstream transcriptionally activating riboswitch, promoting cell aggregation in C. difficile

Quantum measurements of spatial conjugate variables: Displacement and tilt of a Gaussian beam

We consider the problem of measurement of optical transverse profile parameters and their conjugate variable. Using multi-mode analysis, we introduce the concept of detection noise-modes. For Gaussian beams, displacement and tilt are a pair of transverse profile conjugate variables. We experimentally demonstrate their optimal encoding and detection with a spatial homodyning scheme. Using higher order spatial mode squeezing, we show the sub-shot noise measurements for the displacement and tilt of a Gaussian beam.Comment: 3 page