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

Note and Comment

A Criticism of President Hadley\u27s Views on The constitutional Position of Property in America ; Inconsistent Defenses; Vacation of Corporation Directors; Right of the United States to Recover Money Paid on Pension Checks Bearing Forged Indorsements; Damages Recoverable on Stock Broker\u27s Failure to Purchase as Directed

Tracing the Mixing and Movement of Groundwater into Florida Bay with Four Naturally Occurring Radium Isotopes

Proceedings of the 1999 Georgia Water Resources Conference, March 30 and 31, Athens, Georgia.Four naturally occurring isotopes of radium (²²³, ²²⁴, ²²⁶, ²²⁸Ra) have a range in half-life that extends from a few days to over 1,600 years. Unique geochemical attributes make these radium isotopes ideal to examine sediment/water interface exchange processes in coastal waters. Here we present initial radium isotopic data of Florida Bay, a heavily impacted coastal system in south Florida. Florida Bay is a shallow, brackish, semi-enclosed water body that receives most of its limited freshwater supply from the Everglades, principally by surficial water runoff through Trout Creek/Taylor River. Because the entire region is underlain by highly porous Key Largo limestone and due to other hydrologic constraints, there is the possibility that ground water exchange may be significant in Florida Bay. To evaluate the extent of such a subsurface contribution, radium isotopes are being determined in shallow wells, seepage meter sites, and a series of water column samples across the Everglades National Park-Florida Bay boundary. All four radium isotopes were at least an order of magnitude greater in the two shallow well samples than in the water column samples. For example, ²²⁶Ra ranged from about 0.50 dpm L⁻¹ at a salinity of 5 to over 13 dpm L⁻¹ in Well B (salinity = 47.2). Isotopic radium ratios reveal that the well waters (i.e., marine ground water) are geochemically distinct from surficial waters and are regenerated on a time-scale of several days (i.e., ²²⁴Ra/²²³Ra). Results indicate that this radium quartet can be used effectively in Florida Bay to examine the exchange of surficial water and ground water.Sponsored and Organized by: U.S. Geological Survey, Georgia Department of Natural Resources, The University of Georgia, Georgia State University, Georgia Institute of TechnologyThis book was published by the Institute of Ecology, The University of Georgia, Athens, Georgia 30602-2202 with partial funding provided by the U.S. Department of Interior, geological Survey, through the Georgia Water Research Insttitute as authorized by the Water Research Institutes Authorization Act of 1990 (P.L. 101-397). The views and statements advanced in this publication are solely those of the authors and do not represent official views or policies of the University of Georgia or the U.S. Geological Survey or the conference sponsors

Peasant settlers and the ‘civilizing mission’ in Russian Turkestan, 1865-1917

This article provides an introduction to one of the lesser-known examples of European settler colonialism, the settlement of European (mainly Russian and Ukrainian) peasants in Southern Central Asia (Turkestan) in the late nineteenth and early twentieth centuries. It establishes the legal background and demographic impact of peasant settlement, and the role played by the state in organising and encouraging it. It explores official attitudes towards the settlers (which were often very negative), and their relations with the local Kazakh and Kyrgyz population. The article adopts a comparative framework, looking at Turkestan alongside Algeria and Southern Africa, and seeking to establish whether paradigms developed in the study of other settler societies (such as the ‘poor white’) are of any relevance in understanding Slavic peasant settlement in Turkestan. It concludes that there are many close parallels with European settlement in other regions with large indigenous populations, but that racial ideology played a much less important role in the Russian case compared to religious divisions and fears of cultural backsliding. This did not prevent relations between settlers and the ‘native’ population deteriorating markedly in the years before the First World War, resulting in large-scale rebellion in 1916

1953: Abilene Christian College Bible Lectures - Full Text

Delivered in the Auditorium of Abilene Christian College, February, 1953 ABILENE, TEXAS PRICE: $3.00 firm foundation publishing house Box 77 Austin 01, Texa

Energy Flow in the Hadronic Final State of Diffractive and Non-Diffractive Deep-Inelastic Scattering at HERA

An investigation of the hadronic final state in diffractive and non--diffractive deep--inelastic electron--proton scattering at HERA is presented, where diffractive data are selected experimentally by demanding a large gap in pseudo --rapidity around the proton remnant direction. The transverse energy flow in the hadronic final state is evaluated using a set of estimators which quantify topological properties. Using available Monte Carlo QCD calculations, it is demonstrated that the final state in diffractive DIS exhibits the features expected if the interaction is interpreted as the scattering of an electron off a current quark with associated effects of perturbative QCD. A model in which deep--inelastic diffraction is taken to be the exchange of a pomeron with partonic structure is found to reproduce the measurements well. Models for deep--inelastic $ep$ scattering, in which a sizeable diffractive contribution is present because of non--perturbative effects in the production of the hadronic final state, reproduce the general tendencies of the data but in all give a worse description.Comment: 22 pages, latex, 6 Figures appended as uuencoded fil

1968: Abilene Christian College Bible Lectures - Full Text

CROWNING FIFTY YEARS” Being the Fiftieth Annual ABILENE CHRISTIAN COLLEGE BIBLE LECTURES - 1968 J. D. THOMAS, LECTURESHIP DIRECTOR, EDITOR Published by ABILENE CHRISTIAN COLLEGE ACC Station, Abilene, Texas 7960

A comparison of methods for the measurement of the absorption coefficient in natural waters

In the spring of 1992 an optical closure experiment was conducted at Lake Pend Oreille, Idaho. A primary objective of the experiment was to compare techniques for the measurement of the spectral absorption coefficient and other inherent optical properties of natural waters. Daily averages of absorption coefficients measured using six methods are compared at wavelengths of 456, 488, and 532 nm. Overall agreement was within 40% at 456 nm and improved with increasing wavelength to 25% at 532 nm. These absorption measurements were distributed over the final 9 days of the experiment, when bio-optical conditions in Lake Pend Oreille (as indexed by the beam attenuation coefficient cp(660) and chlorophyll a fluorescence profiles) were representative of those observed throughout the experiment. However, profiles of stimulated chlorophyll a fluorescence and beam transmission showed that bio-optical properties in the lake varied strongly on all time and space scales. Therefore environmental variability contributed significantly to deviations between daily mean absorption coefficients measured using the different techniques

“Others-in-Law”: Legalism in the Economy of Religious Differences

Religious legalism encompasses a wide range of attitudes that assign religious meaning to legal content or to legal compliance. The phenomenology of religious legalism is assuming a significant role in various contemporary debates about legal pluralism, accommodation of religious minorities, religious freedom, and so forth. This article revises this conception and the commonplace equation of Judaism and legalism. It suggests that we ought to regard both as part of the economy of religious differences by which religious identities are expressed and defined as alternatives. The common ascription of religious legalism to Judaism (and Islam) is criticized here through a historical analysis of the law-religion-identity matrix in three cultural settings: late ancient Judeo-Hellenic, medieval Judeo–Arabic, and post-Reformation Europe

Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes

<p>Abstract</p> <p>Background</p> <p>Methylmalonic acidemia (MMA), a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition.</p> <p>Methods</p> <p>To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine <it>Mut </it>embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the <it>MUT </it>gene. Enzymatic and expression studies were used to assess the extent of functional correction.</p> <p>Results</p> <p>Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or <it>Mut </it>murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-¹⁴C] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes.</p> <p>Conclusion</p> <p>These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies.</p