gebhart/patrepeval huggingface dataset:
The Sleeping Beauty transposon system: a non-viral vector for gene therapy (2011)

Over the past decade, the Sleeping Beauty (SB) transposon system has been developed as the leading non-viral vector for gene therapy. This vector combines the advantages of viruses and naked DNA. Here we review progress over the last 2 years in vector design, methods of delivery and safety that have supported its use in the clinic. Currently, the SB vector has been validated for ex vivo gene delivery to stem cells, including T-cells for the treatment of lymphoma. Progress in delivery of SB transposons to liver for treatment of various systemic diseases, such as hemophilia and mucopolysaccharidoses types I and VII, has encountered some problems, but even here progress is being made.
Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma (2013)

This 'pathway approach' targeted to cAMP has identified GPCR agonists/antagonists, AC activators (e.g., AC7), PDE inhibitors (e.g., PDE7B) and/or activators or inhibitors of downstream mediators (PKA and Epac, respectively), which might be utilized therapeutically in CLL. Therapy directed at such targets may prove to be clinically useful and may also provide a proof-of-principle of the utility of targeting cAMP signaling in other types of cancer.
The 26 Nudix Hydrolases of Bacillus cereus, a Close Relative of Bacillus anthracis (2004)

The genome of Bacillus cereus contains 26 Nudix hydrolase genes, second only to its closest relative, Bacillus anthracis which has 30. All 26 genes have been cloned, 25 have been expressed, and 21 produced soluble proteins suitable for analysis. Substrates for 16 of the enzymes were identified; these included ADP-ribose, diadenosine polyphosphates, sugar nucleotides, and deoxynucleoside triphosphates. One of the enzymes was a CDP-choline pyrophosphatase, the first Nudix hydrolase active on this substrate. Furthermore, as a result of this and previous work we have identified a new sub-family of the Nudix hydrolase superfamily recognizable by a specific amino acid motif outside of the Nudix box.
Nanosecond Pulsed Electric Fields Have Differential Effects on Cells in The S-Phase (2007)

Nanosecond pulsed electric fields (nsPEFs) are a type of nonthermal, nonionizing radiation that exhibit intense electric fields with high power, but low energy. NsPEFs extend conventional electroporation (EP) to affect intracellular structures and functions and depending on the intensity, can induce lethal and nonlethal cell signaling. In this study, HCT116 human colon carcinoma cells were synchronized to the S-phase or remained unsynchronized, exposed to electric fields of 60 kV/cm with either 60-ns or 300-ns durations, and analyzed for apoptosis and proliferative markers. Several nsPEF structural and functional targets were identified. Unlike unsynchronized cells, S-phase cells under limiting conditions exhibited greater membrane integrity and caspase activation and maintained cytoskeletal structure. Regardless of synchronization, cells exposed to nsPEFs under these conditions primarily survived, but exhibited some turnover and delayed proliferation in cell populations, as well as reversible increases in phosphatidylserine externalization, membrane integrity, and nuclei size. These results show that nsPEFs can act as a nonligand agonist to modulate plasma membrane (PM) and intracellular structures and functions, as well as differentially affect cells in the S-phase, but without effect on cell survival. Furthermore, nsPEF effects on the nucleus and cytoskeleton may provide synergistic therapeutic actions with other agents, such as ionizing radiation or chemotherapeutics that affect these same structures.
Commentary: Why Was Inhaled Insulin a Failure in the Market? (2016)

Just a few years shy of a century ago, a group of Canadian researchers discovered a viable method of extracting insulin, filling a large and critical gap in the therapeutic treatment of diabetes (1). Since then, insulin and its associated delivery devices have become an integral part of the care and management of patients living with diabetes. Shortly after the first insulin injection was successfully delivered, vials of insulin became available commercially. At this time, large glass syringes were used to administer insulin, and each injection required sterilization of the syringe, as well as sharpening of the syringe needle with a pumice stone. Through the years, insulin syringes modernized, but it was not until the 1970s that an alternate delivery system—the insulin pump, used in continuous subcutaneous insulin infusion (CSII) regimens—became available. Fifteen years later, the first insulin pen was introduced to the marketplace, providing evidence that, as time progresses, there is no shortage of innovation in the diabetes arena.

The first two rapid-acting inhaled insulins on the market—Exubera in 2006 and Afrezza in 2014—represented yet another innovation milestone. In theory, inhaled insulin completely eliminated the psychological barriers associated with subcutaneous insulin delivery, such as needle phobia and incorrect injection technique. However, in October 2007, Pfizer withdrew Exubera from the market, and in January 2016, Sanofi withdrew from a $925 million marketing agreement with MannKind for Afrezza; both removals were due to poor sales volume. Although patients and providers have been searching for years for alternatives to injecting insulin, Exubera has already failed, and Afrezza’s destiny is uncertain.

In 2006, Exubera was the first inhaled insulin approved by the U.S. Food and Drug Administration (FDA). It showed noninferiority in efficacy with regard to A1C lowering in both type 1 diabetes (2) and type 2 diabetes (3) compared to mixed regular/NPH …
A HIGH POWER SOLID STATE CIRCUIT BREAKER FOR MILITARY HYBRID ELECTRIC VEHICLE APPLICATIONS (2012)

&lt;title&gt;ABSTRACT&lt;/title&gt; &lt;p&gt;Military vehicle electrical power systems require quickly responding fault protection to prevent mission failure, vehicle damage, or personnel injury. The electromechanical contactors commonly used for HEV protection have slow response and limited cycle life, factors which could result in fuse activation and disabling of the vehicle, presenting a dangerous situation for the soldier. A protection technology not often considered is Solid State Circuit Breakers (SSCB), which have fast response and good reliability. Challenges of extremely high currents and voltages, high temperatures, and harsh conditions have prevented SSCBs from being effective in high power military vehicle electrical systems. Development of an SSCB for military vehicle power systems would increase electrical power system capacity and expand mission capability. The development of a 1.2 kV/200A Silicon-Carbide MOSFET based SSCB for combat HEVs is presented. The key innovation is packaging that minimizes losses, allows high temperature operation, and simplifies cooling requirements. We present results that show response times of less than 5 µs, operational ambient temperatures higher than 125°C, and a current density of 0.4 A/cm&lt;sup&gt;3&lt;/sup&gt;. Our next-generation design will achieve a much greater current density of 12 A/cm&lt;sup&gt;3&lt;/sup&gt; by accommodating up to 2,000 A in a 10 in&lt;sup&gt;3&lt;/sup&gt; package. We present a compelling case that SSCBs overcome electromechanical contactor limitations while providing additional capacity and mission capability.&lt;/p&gt;
Discovering all most specific sentences (2003)

Data mining can be viewed, in many instances, as the task of computing a representation of a theory of a model or a database, in particular by finding a set of maximally specific sentences satisfying some property. We prove some hardness results that rule out simple approaches to solving the problem.The a priori algorithm is an algorithm that has been successfully applied to many instances of the problem. We analyze this algorithm, and prove that is optimal when the maximally specific sentences are "small". We also point out its limitations.We then present a new algorithm, the Dualize and Advance algorithm, and prove worst-case complexity bounds that are favorable in the general case. Our results use the concept of hypergraph transversals. Our analysis shows that the a priori algorithm can solve the problem of enumerating the transversals of a hypergraph, improving on previously known results in a special case. On the other hand, using results for the general case of the hypergraph transversal enumeration problem, we can show that the Dualize and Advance algorithm has worst-case running time that is sub-exponential to the output size (i.e., the number of maximally specific sentences).We further show that the problem of finding maximally specific sentences is closely related to the problem of exact learning with membership queries studied in computational learning theory.
Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing (2013)

Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.
A surface-exposed region of G(salpha) in which substitutions decrease receptor-mediated activation and increase receptor affinity. (2000)

The mechanism by which receptors activate G proteins is unclear because a connection between the receptor and the nucleotide binding site has not been established. To investigate this mechanism, we evaluated the roles in receptor interaction of three potential receptor contact sites in alpha(s): the alpha2/beta4, alpha3/beta5, and alpha4/beta6 loops. Substitutions of alpha(i2) homologs for alpha(s) residues in the alpha2/beta4 loop and alanine substitutions of residues in the alpha4/beta6 loop do not affect activation by the beta(2)-adrenergic receptor. However, replacement of five alpha(s) residues in the alpha3/beta5 loop region with the homologous alpha(i2) residues decreases receptor-mediated activation of alpha(s) and increases the affinity of G(s) for this receptor. The substitutions do not alter guanine nucleotide binding or hydrolysis, or activation by aluminum fluoride, indicating that the effects on receptor interaction are not due to a destabilization of the guanine-nucleotide bound state. In a model of the receptor-G protein complex, the alpha3/beta5 loop maps near the second and third intracellular loops of the receptor. The effects of the alpha3/beta5 substitutions suggest that the wild-type residues may be receptor contact sites that are optimized to ensure the reversibility of receptor-G protein interactions. Furthermore, the alpha3/beta5 region corresponds to an exchange factor contact site in both EF-Tu and Ras, suggesting that the mechanisms by which seven-transmembrane receptors and exchange factors catalyze nucleotide exchange may share common elements.
Renal fibrosis: an update (2001)

Tubulointerstitial fibrosis invariably accompanies the course of chronic renal failure towards end-stage renal disease. Tubular epithelial cells, the predominant cell type in the tubulointerstitium, are increasingly being recognized for playing a dominant role as mediators of renal fibrogenesis. Tubular epithelial cells become activated either by the glomerular ultrafiltrate from their apical side or by mononuclear cells from their basolateral side. They initiate the scarring process by secreting chemokines, which in return attract mononuclear cells as well as growth factors that stimulate interstitial fibroblasts. In later phases of renal fibrogenesis, cellular changes of tubular epithelial cells contribute to the chronic impairment of renal function. Whereas tubular epithelial cells react by proliferation or hypertrophy to initial stimuli, they may undergo apoptosis or transdifferentiate into fibroblasts, and thus contribute to tubular atrophy in later stages of progressive renal disease. Resident interstitial fibroblasts are also important in renal fibrogenesis, and recent research has demonstrated that these cells are much more heterogeneous than expected. Cytokines such as fibroblast growth factor type 2 and epithelial growth factor have been shown to be pro-fibrogenic, whereas hepatocyte growth factor and bone morphogenic protein type 7 may inhibit fibrogenesis. Despite recent progress, further research is mandatory for a better understanding and the development of novel therapeutic approaches.
Ionic Conductivity of Lithium Orthosilicate—Lithium Phosphate Solid Solutions (1977)

Lithium ion conductivity in solid solutions formed between and has been measured as a function of temperature and composition using a‐c techniques. Highest conductivities were found at 50 and 60 mole percent (m/o) phosphate. Empirical conductivity parameters are presented and qualitatively analyzed in terms of structural and compositional effects. Unit cell parameters have been determined across the entire range of solid solution by x‐ray powder diffraction.
Synchronous implementation of a counterflow pipeline processor (1996)

The counterflow pipeline principle was originated by Sproull (1994) as an architecture for asynchronous processor design. As such, it offers many useful properties including local control, local message passing, and an overall simple design methodology. We have taken these same ideas and used them in the design of a synchronous processor. Since the speed of today's processors is being limited more and more by the global signal routing, an architecture which seeks to limit these may indeed result in a significant speed increase. We intend to show that the local interchange of information and simple design can allow for longer pipelines and increased processor throughput.
Report of the National Pituitary Agency Collaborative Study on the Radioimmunoassay of FSH and LH1 (1968)

THE NATIONAL Pituitary Agency (NPA) has conducted a collaborative study of the radioimmunoassay of human follicle stimulating hormone (HFSH) and human luteinizmg hormone (HLH) in order to characterize and make available the necessary reagents for use in clinical investigation. Before suitable reagents can be distributed for clinical investigation, three conditions must be defined: 1) specificity of the antisera, evaluated by comparison of the results obtained from the radioimmunoassay technique and those obtained from the bioassay technique, 2) the applicability of the radioimmunoassay technique to measurements in serum, 3) the designation, establishment and availability of suitable standards for the expression of the radioimmunoassay results. Several groups of investigators collaborated in an attempt to define these three conditions. Four human pituitary gland extracts differing widely in FSH/LH ratio and “immunochemical grade” HFSH and HLH were prepared by L. E. Reichert (LER series); a second “immunochemical grade” HLH was prepared by A. F. Parlow (AFP series).
Characterization of Dysfunctional Myocardium by Positron Emission Tomography and Magnetic Resonance (2003)

Metabolism and tissue composition discriminate various classes of dysfunctional myocardium. Most metabolically viable segments with a thick viable rim on ce-MR recover function after revascularization, whereas all other classes showed low recovery rates of contractile function.
Testing the NKT cell hypothesis of human IDDM pathogenesis (2002)

Defects in IL-4–producing CD1d-autoreactive NKT cells have been implicated in numerous Th1-mediated autoimmune diseases, including diabetes, multiple sclerosis, rheumatoid arthritis, lupus, and systemic sclerosis. Particular attention has been focused on autoimmune insulin-dependent diabetes mellitus (IDDM) because nonobese diabetic (NOD) mice and humans with IDDM are both reported to express severe deficiencies in the frequency and Th2 functions of NKT cells. Furthermore, experimental manipulations of the NKT defect in the NOD mouse induced corresponding changes in disease. Taken together, these converging studies suggested a general role of NKT cells in natural protection against destructive autoimmunity. However, in previous reports the identification of NKT cells was based on indirect methods. We have now devised a direct, highly specific CD1d tetramer–based methodology to test whether humans with IDDM have associated NKT cell defects. Surprisingly, although we find marked and stable differences in NKT cells between individuals, our study of IDDM patients and healthy controls, including discordant twin pairs, demonstrates that NKT cell frequency and IL-4 production are conserved during the course of IDDM. These results contradict previous conclusions and refute the hypothesis that NKT cell defects underlie most autoimmune diseases.
Comparative Pharmacokinetic Properties of Murine Monoclonal Antibody A7 Modified with Neocarzinostatin, Dextran and Polyethylene Glycol (1991)

The murine monoclonal antibody A7 (Mab A7) was chemically modified with several macromolecules: dextran, polyethylene glycol and the anti-cancer polypeptide neocarzinostatin. The pharmacokinetic properties of the combinations were subsequently examined. Radioimmunoassay revealed that all preparations retained their antigen-binding activities. The Mab A7-neocarzinostatin conjugate was cleared from the blood circulation with a kinetic pattern almost identical to that of the parent Mab A7. Of the three preparations, Mab A7-dextran (A7-Dx) was removed the most rapidly from the circulation. Mab A7-polyethylene glycol (A7-PEG) exhibited the slowest blood clearance curve, with twice the half life of the parent Mab A7 in the circulation. In normal organ distributions, A7-Dx exhibited the highest liver, spleen and kidney uptake, and A7-PEG showed the lowest uptake, when expressed as tissue:blood ratio. Although A7-Dx exhibited lower tumor uptake, there was no significant difference among the three conjugates in tumor-bearing nude mice. A7-PEG seems to be a good candidate for targeted cancer therapy using antibody due to its high blood retention but low normal organ uptake.
The economic background [March 1997] (1997)

Growth in 1995 has slowed down in the world economy with the exception of the dynamic Asian economies. G7 average growth has fallen from 2.8%p.a. in 1994 to 2.3%p.a. in 1995, and is forecast to remain at this level in 1996 before rising to 1994 levels in 1998.
Visual vibrometry: Estimating material properties from small motions in video (2015)

The estimation of material properties is important for scene understanding, with many applications in vision, robotics, and structural engineering. This paper connects fundamentals of vibration mechanics with computer vision techniques in order to infer material properties from small, often imperceptible motion in video. Objects tend to vibrate in a set of preferred modes. The shapes and frequencies of these modes depend on the structure and material properties of an object. Focusing on the case where geometry is known or fixed, we show how information about an object's modes of vibration can be extracted from video and used to make inferences about that object's material properties. We demonstrate our approach by estimating material properties for a variety of rods and fabrics by passively observing their motion in high-speed and regular framerate video.
High-Throughput Site-Directed Mutagenesis using Oligonucleotides Synthesized on DNA Chips (2005)

Site-directed mutagenesis has greatly helped researchers both to understand the precise role of specific residues in coding sequences and to generate variants of proteins that have acquired new characteristics. Today's demands for more complete functional cartographies of proteins and advances in selection and screening technologies require that site-directed mutagenesis be adapted for high-throughput applications. We describe here the first generation of a library of single and multiple site-directed mutants using a mixture of oligonucleotides synthesized on DNA chips. We have used the human interleukin 15 (IL15) gene as a model, of which 37 codons were simultaneously targeted for substitution by any of eight possible codons. Ninety-six clones were sequenced, exhibiting a broad spectrum of targeted substitutions over the whole gene length with no unwanted mutations. Libraries produced using such pools of oligonucleotides open new perspectives to direct the evolution of proteins in vitro, by enabling the simple, rapid, and cost-effective generation of large tailor-made genetic diversities from any gene.
d‐Polyarginine Lipopeptides as Intestinal Permeation Enhancers (2018)

An estimated 285 million people were living with diabetes in 2010, and this number is expected to reach 440 million by 2030. Current treatment of this disease involves the intradermal injection of insulin analogues. Many alternative administration routes have been proposed, the oral route being the most widely studied. One of the most interesting approaches for insulin delivery is the use of permeation enhancers to increase its transport across the gastrointestinal tract (GIT). Cell-penetrating peptides (CPPs) are a remarkable example of this family of compounds. Another alternative is the use of medium-chain fatty acids (MCFAs) to temporally disrupt the tight junctions of the GIT, thereby allowing greater drug transport. A combination of both strategies can provide a synergistic way to increase drug transport through the GIT. In this study we evaluated the complexation of insulin glulisine, an insulin analogue administered subcutaneously or intravenously in clinical practice, with a well-known CPP modified with the MCFA lauric acid. We prepared several formulations, examined their stability, and tested the best candidates in an intestinal cell-based model. In particular, two compounds (C<sub>12</sub> -r<sub>4</sub> and C<sub>12</sub> -r<sub>6</sub> ) were found to significantly increase the transport of insulin, and therefore show promise as a new delivery system worthy of further evaluation.