gebhart/patrepeval huggingface dataset:
Functional Characterization of the Transactivation Properties of the PDX-1 Homeodomain Protein (1997)

Pancreas formation is prevented in mice carrying a null mutation in the PDX-1 homeoprotein, demonstrating a key role for this factor in development. PDX-1 can also bind to and activate transcription from cis-acting regulatory sequences in the insulin and somatostatin genes, which are expressed in pancreatic islet beta and delta cells, respectively. In this study, we compared the functional properties of PDX-1 with those of the closely related Xenopus homeoprotein XIHbox8. Analysis of chimeras between PDX-1, XIHbox8, and the DNA-binding domain of the Saccharomyces cerevisiae transcription factor GAL4 revealed that their transactivation domain was contained within the N-terminal region (amino acids 1 to 79). Detailed mutagenesis of this region indicated that transactivation is mediated by three highly conserved sequences, spanning amino acids 13 to 22 (subdomain A), 32 to 38 (subdomain B), and 60 to 73 (subdomain C). These sequences were also required by PDX-1 to synergistically activate insulin enhancer-mediated transcription with another key insulin gene activator, the E2A-encoded basic helix-loop-helix E2-5 and E47 proteins. These results indicated that N-terminal sequences conserved between the mammalian PDX-1 and Xenopus XIHbox8 proteins are important in transcriptional activation. Stable expression of the PDX-1 deltaABC mutant in the insulin- and PDX-1-expressing betaTC3 cell line resulted in a threefold reduction in the rate of endogenous insulin gene transcription. Strikingly, the level of the endogenous PDX-1 protein was reduced to very low levels in these cells. These results suggest that PDX-1 is not absolutely essential for insulin gene expression in betaTC3 cells. We discuss the possible significance of these findings for insulin gene transcription in islet beta cells.
Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease (2011)

Xenotransplantation of acute myeloid leukemia (AML) into immunodeficient mice has been critical for understanding leukemogenesis in vivo and defining self-renewing leukemia-initiating cell subfractions (LICs). Although AML-engraftment capacity is considered an inherent property of LICs, substrains of NOD/SCID mice that possess additional deletions such as the IL2Rγc(null) (NSG) have been described as a more sensitive recipient to assay human LIC function. Using 23 AML-patient samples, 39% demonstrated no detectable engraftment in NOD/SCID and were categorized as AMLs devoid of LICs. However, 33% of AML patients lacking AML-LICs were capable of engrafting NSG recipients, but produced a monoclonal T-cell proliferative disorder similar to T-ALL. These grafts demonstrated self-renewal capacity as measured by in vivo serial passage and were restricted to CD34-positive fraction, and were defined as LICs. Molecular analysis for translocations in MLL genes indicated that these AML patient-derived LICs all expressed the MLL-AFX1 fusion product. Our results reveal that the in vivo human versus xenograft host microenvironment dictates the developmental capacity of human LICs residing in a small subset of patients diagnosed with AML harboring MLL mutations. These findings have implications both for the basic biology of CSC function, and for the use of in vivo models of the leukemogenic process in preclinical or diagnostic studies.
‘GM‐gene‐deletor’: fused loxP‐FRT recognition sequences dramatically improve the efficiency of FLP or CRE recombinase on transgene excision from pollen and seed of tobacco plants (2007)

Pollen- and seed-mediated transgene flow is a concern in plant biotechnology. We report here a highly efficient 'genetically modified (GM)-gene-deletor' system to remove all functional transgenes from pollen, seed or both. With the three pollen- and/or seed-specific gene promoters tested, the phage CRE/loxP or yeast FLP/FRT system alone was inefficient in excising transgenes from tobacco pollen and/or seed, with no transgenic event having 100% efficiency. When loxP-FRT fusion sequences were used as recognition sites, simultaneous expression of both FLP and CRE reduced the average excision efficiency, but the expression of FLP or CRE alone increased the average excision efficiency, with many transgenic events being 100% efficient based on more than 25,000 T(1) progeny examined per event. The 'GM-gene-deletor' reported here may be used to produce 'non-transgenic' pollen and/or seed from transgenic plants and to provide a bioconfinement tool for transgenic crops and perennials, with special applicability towards vegetatively propagated plants and trees.
A hybrid bioartificial liver composed of multiplated hepatocyte monolayers. (1989)

Monolayer cultures of hepatocytes were shown to have good function when compared with suspended cells. The authors manufactured a new hybrid artificial liver containing hepatocyte monolayers and evaluated its function. Hepatocytes isolated from an adult dog liver were cultured on collagen coated borosilicated glass (10 X 20 X 0.04 cm). A long-stroke artificial liver module was constructed by stacking 200 glass plates bearing hepatocytes, which were viable and functioned well during 4 weeks in perfusion culture; glyconeogenesis = 110 ng/micrograms DNA/min, urea synthesis = 3.6 ng/micrograms DNA/min and albumin synthesis = 29 micrograms/10(6) cells/day at the 5th day of perfusion. The levels were maintained for 2 weeks. The new device was applied to anhepatic dogs (Group 3) and compared with untreated (Group 1) and plasma exchange dogs (Group 2). The survival times were 21.3 +/- 5.6 hours in Group 1 (N = 6), 27.8 +/- 4.0 hours in Group 2 (N = 3), and 55.0 +/- 10.3 hours in Group 3 (N = 4). The longest survival was 65 hours. Serum ammonia increased to over 2,000 micrograms/dl after 12 hours in Groups 1 and 2, but remained under 400 micrograms/dl in Group 3. This new type of hybrid system may be a pilot design for the complete artificial liver.
HIV-1 Membrane Fusion (2000)

The AIDS pandemic is spreading unchecked in many parts of the world. Currently available anti-viral regimens are plagued by their high cost, by serious side effects in a significant minority of recipients, and by the increasing problems of drug-resistant HIV variants. Fortunately, rapid advances in
Experimental Characterization and Modeling of Pulsed MOCVD with Ultrasonic Atomization of Liquid Precursor (2001)

Layers of titania were deposited on nickel substrates by an innovative process called pulsed MOCVD. Variation in growth rate, conversion efficiency, crystallographic orientation, and microstructure were studied as functions of precursor injection rate and deposition temperature. Pulsed-MOCVD was found to provide a great deal of control of microstructure, optimization for high growth rates, and high conversion efficiency. A Langmuir derivation of mass balance on the growing film surface with a surface saturation condition was used to model the deposition.
Proteomic Analysis of Human Immunodeficiency Virus Using Liquid Chromatography/Tandem Mass Spectrometry Effectively Distinguishes Specific Incorporated Host Proteins (2006)

A major challenge to studying virus-incorporated host proteins is the fact that they are not encoded by the viral genome. We used Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) on whole virions to obtain a snapshot of the HIV-1 proteome. We identified known viral and host-cellular proteins and also identified novel components of HIV-1 and confirm these by traditional biochemical methods. Our comparison of wild-type and mutant viruses demonstrates that LC-MS/MS has the specificity to distinguish the presence/absence of a single host protein in intact virions.
Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma (2008)

We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon alpha-2b thrice weekly or to 3 MU interferon alpha-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P= .006) and overall responses (68% vs 50%; P= .002) compared with MP. Time to progression (21.2 vs 29.1 months; P= .2), and progression-free survival was similar (16.7 vs 20.7 months; P= .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P= .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.
2-Chloropropionamide As a Low-Reactivity Electrophile for Irreversible Small-Molecule Probe Identification (2017)

Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery. Here, we report the synthesis and evaluation of a library of small molecules containing the 2-chloropropionamide functionality, which we demonstrate is less reactive than typical acrylamide electrophiles. Although many library members do not appear to label proteins in cells, we identified S-CW3554 as selectively labeling protein disulfide isomerase and inhibiting its enzymatic activity. Subsequent profiling of the library against five diverse cancer cell lines showed unique cytotoxicity for S-CW3554 in cells derived from multiple myeloma, a cancer recently reported to be sensitive to PDI inhibition. Our novel PDI inhibitor highlights the potential of 2-chloropropionamides as weak and stereochemically tunable electrophiles for covalent drug discovery.
Phytotoxicity of Acetohydroxyacid Synthase Inhibitors Is Not Due to Accumulation of 2-Ketobutyrate and/or 2-Aminobutyrate (1993)

Acetohydroxyacid synthase (AHAS) is the site of action of herbicides of different chemical classes, such as imidazolinones, sulfonylureas, and triazolopyrimidines. Inhibition of AHAS causes the accumulation of 2-ketobutyrate (2-KB) and 2-aminobutyrate (2-AB) (the transamination product of 2-KB), and it has been proposed that the phytotoxicity of these inhibitors is due to this accumulation. Experiments were done to determine the relationship between accumulation of 2-KB and 2-AB and the phytotoxicity of imazaquin to maize (Zea mays). Imazaquin concentrations that inhibit growth of maize plants also cause the accumulation of 2-KB and 2-AB in the shoots. Supplementation of imazaquin-treated plants with isoleucine reduced the pools of 2-KB and 2-AB in the plant but did not protect plants from the growth inhibitory effects of imazaquin. Conversely, feeding 2-AB to maize plants increased 2-KB and 2-AB pools to much higher levels than those observed in imazaquin-treated plants, yet such high pools of 2-KB and 2-AB in the plant had no significant effect on growth. These results conclusively demonstrate that growth inhibition following imazaquin treatment is not due to accumulation of 2-KB and/or 2-AB in plants. Changes in the amino acid profiles after treatment with imazaquin suggest that starvation for the branched-chain amino acids may be the primary cause of growth retardation of maize.
Effect of colony stimulating factor on murine macrophages. Induction of antitumor activity. (1982)

Colony stimulating factor (CSF) was assessed for its capacity to stimulate antitumor activity in macrophages. Murine peritoneal macrophages incubated with CSF for 48 h inhibited [3H[thymidine (TdR) incorporation by P815 tumor cells to approximately 20% of control values. Inhibition of CSF-stimulated macrophages was significantly greater than inhibition by unstimulated macrophages (P less than 0.001). CSF had little direct effect on the proliferation of either tumor cells or macrophages alone, indicating that the antitumor activity of CSF was mediated by macrophages. it is unlikely that impurities in the CSF preparations were responsible for the effect since CSF that had been purified to homogeneity was as active as crude preparations. Furthermore the activity of CSF on macrophages was blocked by addition of purified anti-CSF antibodies. In addition to being tumoristatic, CSF-stimulated macrophages were tumoricidal as determined by a tumor colony growth assay. Tumor cells that had been incubated with CSF-stimulated macrophages showed a significant reduction in tumor colony-forming units (P less than 0.01). Thus, in addition to its effect on hemopoietic stem cells, CSF induces certain effector functions in mature macrophages that may enhance endogenous antitumor host defenses.
Monolithic super-bright red resonant cavity light-emitting diode grown by solid source molecular beam epitaxy (1998)

Monolithic super-bright resonant-cavity light-emitting diode operating at /spl lambda/=663 nm has been developed. The diode consisted of a 1/spl lambda/-thick AlGaInP active region sandwiched between AlAs-AlGaAs distributed Bragg reflectors. The device structure was grown by solid source molecular beam epitaxy. The current aperture of the emitter was created by lateral selective wet thermal oxidation. A record-high peak wall-plug efficiency of 2.2% and a continuous-wave output power of 1.4 mW were attained without heatsinking at room temperature from a diode having a diameter of 80 μm. The emission linewidth was as narrow as 4.5 nm.
Ceramide: an intracellular mediator of apopotosis and growth supression (1996)

Ceramide is an endogenous lipid molecule generated by hydrolysis of membrane sphingomyelin, in response to cellular stimulation by hormones and cytokines. Ceramide appears to have a role in mediating biological responses in a wide variety of cell types. These responses are generally considered anti-proliferative, but endpoints are varied and include differentiation, growth inhibition, senescence and apoptotic cell death. Mechanisms for ceramide action involve regulation of protein phosphorylation via stimulation of a serine/threonine protein phosphatase, a proline-directed kinase and possibly other direct and/or indirect targets.
Real-time enveloping with rotational regression (2007)

Enveloping, or the mapping of skeletal controls to the deformations of a surface, is key to driving realistic animated characters. Despite its widespread use, enveloping still relies on slow or inaccurate deformation methods. We propose a method that is both fast, accurate and example-based. Our technique introduces a rotational regression model that captures common skinning deformations such as muscle bulging, twisting, and challenging areas such as the shoulders. Our improved treatment of rotational quantities is made practical by model reduction that ensures real-time solution of least-squares problems, independent of the mesh size. Our method is significantly more accurate than linear blend skinning and almost as fast, suggesting its use as a replacement for linear blend skinning when examples are available.
Mast cell chymase limits the cardiac efficacy of Ang I–converting enzyme inhibitor therapy in rodents (2010)

Ang I-converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang II-forming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor-mediated increase in LV ISF chymase activity that was not observed in mast cell-deficient KitW/KitW-v mice. In chronic ACE inhibitor-treated mast cell-sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.
Synthesis and Selective Cyclooxygenase-2 Inhibitory Activity of a Series of Novel, Nitric Oxide Donor-Containing Pyrazoles (2004)

The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
The IBM Blue Gene/Q Compute Chip (2011)

Blue Gene/Q aims to build a massively parallel high-performance computing system out of power-efficient processor chips, resulting in power-efficient, cost-efficient, and floor-space- efficient systems. Focusing on reliability during design helps with scaling to large systems and lowers the total cost of ownership. This article examines the architecture and design of the Compute chip, which combines processors, memory, and communication functions on a single chip.
Synthesis of the Bestmann-Ohira Reagent (2006)

The conversion of an aldehyde to a terminal alkyne by means of a one-carbon chain extension is a key reaction in organic synthesis. By using dimethyl 1-diazo-2-oxopropylphosphonate, the Bestmann-Ohira reagent, the transformation can be achieved in one pot. A reliable, convenient sequence for the preparation of the Bestmann-Ohira reagent is described.
Oligonucleotide-based strategies to combat polyglutamine diseases (2014)

Considerable advances have been recently made in understanding the molecular aspects of pathogenesis and in developing therapeutic approaches for polyglutamine (polyQ) diseases. Studies on pathogenic mechanisms have extended our knowledge of mutant protein toxicity, confirmed the toxicity of mutant transcript and identified other toxic RNA and protein entities. One very promising therapeutic strategy is targeting the causative gene expression with oligonucleotide (ON) based tools. This straightforward approach aimed at halting the early steps in the cascade of pathogenic events has been widely tested for Huntington's disease and spinocerebellar ataxia type 3. In this review, we gather information on the use of antisense oligonucleotides and RNA interference triggers for the experimental treatment of polyQ diseases in cellular and animal models. We present studies testing non-allele-selective and allele-selective gene silencing strategies. The latter include targeting SNP variants associated with mutations or targeting the pathologically expanded CAG repeat directly. We compare gene silencing effectors of various types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing. We discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases.
A comparison of PGE2 effects on human suppressor cell function and on interleukin 2 function. (1982)

Abstract Two possible mechanisms of prostaglandin E2- (PGE2) mediated inhibition of human blood mononuclear cell (PBMC) proliferation were compared to determine whether PGE2 suppressed these responses indirectly by activation of a suppressor cell, directly by inhibition of interleukin 2 (IL 2) responses, or by a combination of the two mechanisms. The first mechanism is unlikely since depletion of phenotypically defined suppressor cell populations (TG+ or OKT8+ cells) from PBMC did not diminish the PGE2-mediated inhibition of PHA responses. For example, 10 ng/ml PGE2 suppressed the response of ER+T cells by an average of 61%, and the response of TG– cells was suppressed by an average of 62%. Similarly, 10 ng/ml PGE2 suppressed the PHA response of OKT8– PBMC by an average of 40% and the response of unseparated PBMC by an average of 34%. Experiments were then performed to distinguish direct effects of PGE2 from possible suppressor cell activation. PBMC were precultured with PGE2 for 24 hr, washed, and tested for suppressor cell function in the absence of additional PGE2. PBMC precultured with PGE2 did not suppress the PHA response of freshly isolated autologous PBMC, whereas PBMC precultured with Con A (a positive control) suppressed the PHA response of fresh PBMC by an average of 47%. The influence of PGE2 on IL 2-dependent proliferation and IL 2 production was then examined. PGE2 inhibited proliferation of IL 2-dependent cell lines as measured by enumeration of viable cells and by 3-thymidine incorporation. In addition, PGE2 suppressed the quantity of IL 2 produced by PHA-stimulated PBMC. For example, 10 ng/ml PGE2 reduced by 50% the amount of IL 2 activity produced by PBMC. We conclude that PGE2 directly suppressed human lymphocyte proliferation by interfering with both the production of IL 2 and IL 2-dependent proliferation. Furthermore, there was no evidence that PGE2 induced suppressor cell function in man.