gebhart/patrepeval huggingface dataset:
FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts. (1993)

Avian progesterone receptor complexes contain five major co-purifying proteins, including hsp90, hsp70, and a 23-kDa protein. The other receptor-associated proteins, p50 and p54, share amino acid sequence similarities with a 52-59-kDa component (p59, hsp56, or FKBP52) of mammalian steroid receptor complexes that is also a member of the FK506-binding proteins (FKBP) family of immunophilins. We show here that p50, but not p54, cross-reacts with a rabbit antiserum prepared against human FKBP52. Both p50 and p54 bind an FK506 affinity resin at 0.5 M KCl, but only p50 binds efficiently in low salt conditions. Glycerol density gradient analyses show that both p50 and p54 exist predominantly in oligomeric complexes at low ionic strength. The poor retention of p54 on FK506 resin at low ionic strength compared with the high retention of p50 suggests that these proteins may largely exist in separate complexes and may interact with other proteins, such as progesterone receptor, in distinctive manners. In HeLa cell extracts, a 55-kDa FK506-binding protein, distinct from FKBP52, cross-reacts with anti-p54 antibody FF1. We conclude that p50 is avian FKBP52, whereas p54 and the 55-kDa human FF1 antigen are FKBP54, a novel immunophilin.
Extracellular proteases from Xanthomonas campestris pv. campestris, the black rot pathogen (1990)

Two proteases (PRT1 and PRT2) were fractionated from culture supernatants of wild-type Xanthomonas campestris pv. campestris by cation-exchange chromatography on SP-5PW. Inhibitor experiments showed that PRT 1 was a serine protease which required calcium ions for activity or stability or both and that PRT 2 was a zinc-requiring metalloprotease. PRT 1 and PRT 2 showed different patterns of degradation of beta-casein. The two proteases comprised almost all of the extracellular proteolytic activity of the wild type. A protease-deficient mutant which lacked both PRT 1 and PRT 2 showed considerable loss of virulence in pathogenicity tests when bacteria were introduced into mature turnip leaves through cut vein endings. This suggests that PRT 1 and PRT 2 have a role in black rot pathogenesis.
Impact of interference on multi-hop wireless network performance (2003)

In this paper, we address the following question: given a specific placement of wireless nodes in physical space and a specific traffic workload, what is the maximum throughput that can be supported by the resulting network? Unlike previous work that has focused on computing asymptotic performance bounds under assumptions of homogeneity or randomness in the network topology and/or workload, we work with any given network and workload specified as inputs.A key issue impacting performance is wireless interference between neighboring nodes. We model such interference using a conflict graph, and present methods for computing upper and lower bounds on the optimal throughput for the given network and workload. To compute these bounds, we assume that packet transmissions at the individual nodes can be finely controlled and carefully scheduled by an omniscient and omnipotent central entity, which is unrealistic. Nevertheless, using ns-2 simulations, we show that the routes derived from our analysis often yield noticeably better throughput than the default shortest path routes even in the presence of uncoordinated packet transmissions and MAC contention. This suggests that there is opportunity for achieving throughput gains by employing an interference-aware routing protocol.
Mechanism of Adrenal Insufficiency Following Trauma and Severe Hemorrhage (1999)

Sustained increase in plasma corticosterone levels following hemorrhage and resuscitation may be, in part, due to the decreased hepatic 11beta-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhage.
The Phosphotyrosine Phosphatase PTP1D, but not PTP1C, Is an Essential Mediator of Fibroblast Proliferation Induced by Tyrosine Kinase and G Protein-coupled Receptors (1995)

PTP1C and PTP1D are non-transmembrane protein-tyrosine phosphatases (PTPs), which contain two src homology-2 domains. These enzymes are believed to play a role in regulating downstream signaling from receptors with intrinsic tyrosine kinase activity. The present study describes the tyrosine phosphorylation and the catalytic activity of both PTPs in CCL39 cells, a Chinese hamster lung fibroblast cell line, upon addition of a variety of growth factors. We demonstrate that PTP1C activity was significantly stimulated by insulin and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate but was not influenced by serum, platelet-derived growth factor (PDGF), or alpha-thrombin. However, tyrosine phosphorylation of PTP1C was increased in response to insulin, PDGF, and alpha-thrombin. PTP1D activity was slightly stimulated by insulin and 12-O-tetradecanoylphorbol-13-acetate but was significantly inhibited by serum, PDGF, and alpha-thrombin, although tyrosine phosphorylation is increased in response to these agonists. Mitogen-activated protein kinase phosphorylated PTP1C and PTP1D in in vitro kinase assays, suggesting that both PTPs are target proteins for mitogen-activated protein kinase. We also show that overexpression of PTP1C or PTP1D had no effect on DNA synthesis stimulated by different growth factors. However, a mutated inactive form of PTP1D strongly inhibited the stimulatory effects of both PDGF and alpha-thrombin on early gene transcription and DNA synthesis. These results demonstrate for the first time that PTP1C and PTP1D may participate in signal transduction but in different manners and that only PTP1D is a positive mediator of mitogenic signals induced by both tyrosine kinase receptors and G protein-coupled receptors in fibroblasts.
Transient dynamics simulations (1996)

Transient dynamics simulations are commonly used to model phenomena such as car crashes, underwater explosions, and the response of shipping containers to high-speed impacts. Physical objects in such a simulation are typically represented by Lagrangian meshes because the meshes can move and deform with the objects as they undergo stress. Fluids (gasoline, water) or fluid-like materials (earth) in the simulation can be modeled using the techniques of smoothed particle hydrodynamics. Implementing a hybrid mesh/particle model on a massively parallel computer poses several difficult challenges. One challenge is to simultaneously parallelize and load-balance both the mesh and particle portions of the computation. A second challenge is to efficiently detect the contacts that occur within the deforming mesh and between mesh elements and particles as the simulation proceeds. These contacts impart forces to the mesh elements and particles which must be computed at each timestep to accurately capture the physics of interest. In this paper we describe new parallel algorithms for smoothed particle hydrodynamics and contact detection which turn out to have several key features in common. Additionally, we describe how to join the new algorithms with traditional parallel finite element techniques to create an integrated particle/mesh transient dynamics simulation. Our approach to this problem differs from previous work in that we use three different parallel decompositions, a static one for the finite element analysis and dynamic ones for particles and for contact detection. We have implemented our ideas in a parallel version of the transient dynamics code PRONTO-3D and present results for the code running on a large Intel Paragon.
Preliminary experience with oral dexmedetomidine for procedural and anesthetic premedication (2005)

These preliminary data suggest that dexmedetomidine may be an effective oral premedicant prior to anesthesia induction or procedural sedation. We found that it was effective even in patients with neurobehavioral disorders in whom previous attempts at sedation had failed.
Targeting histone deacetylases for the treatment of cancer and inflammatory diseases (2006)

Histone deacetylases (HDACs) are involved in chromatin remodeling and modification of nonhistone transcription regulatory proteins, thus modulating the expression of genes important for complex biological events. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation may be implicated in the pathogenesis of various diseases, including cancer and inflammatory diseases. A significant number of HDAC inhibitors (HDIs) have been developed in the past decade. These inhibitors demonstrate strong anti-neoplastic effects in vitro and in vivo by inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. More than a dozen HDIs are currently being evaluated in phase I-II clinical trials in patients with solid and hematological malignancies, and some have already shown promising activity with low toxicity. HDIs also exhibit strong anti-inflammatory effects in vitro and in animal models for various inflammatory diseases, thus representing a new class of promising agents for treating inflammatory diseases. This review provides an overview of HDACs in gene regulation, HDIs for cancer therapy and for potential treatment of inflammatory diseases, and future perspectives.
Metabolic cleavage of cell-penetrating peptides in contact with epithelial models: human calcitonin (hCT)-derived peptides, Tat(47–57) and penetratin(43–58) (2004)

We assessed the metabolic degradation kinetics and cleavage patterns of some selected CPP (cell-penetrating peptides) after incubation with confluent epithelial models. Synthesis of N-terminal CF [5(6)-carboxyfluorescein]-labelled CPP, namely hCT (human calcitonin)-derived sequences, Tat(47-57) and penetratin(43-58), was through Fmoc (fluoren-9-ylmethoxycarbonyl) chemistry. Metabolic degradation kinetics of the tested CPP in contact with three cell-cultured epithelial models, MDCK (Madin-Darby canine kidney), Calu-3 and TR146, was evaluated by reversed-phase HPLC. Identification of the resulting metabolites of CF-hCT(9-32) was through reversed-phase HPLC fractionation and peak allocation by MALDI-TOF-MS (matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry) or direct MALDI-TOF-MS of incubates. Levels of proteolytic activity varied highly between the investigated epithelial models and the CPP. The Calu-3 model exhibited the highest proteolytic activity. The patterns of metabolic cleavage of hCT(9-32) were similar in all three models. Initial cleavage of this peptide occurred at the N-terminal domain, possibly by endopeptidase activity yielding both the N- and the C-terminal counterparts. Further metabolic degradation was by aminopeptidase, endopeptidase and/or carboxypeptidase activities. In conclusion, when in contact with epithelial models, the studied CPP were subject to efficient metabolism, a prerequisite of cargo release on the one hand, but with potential for premature cleavage and loss of the cargo as well on the other. The results, particularly on hCT(9-32), may be used as a template to suggest structural modifications towards improved CPP performance.
Cytokine modulators for allergic diseases (2001)

Cytokines play a critical role in orchestrating and perpetuating inflammation in allergic diseases and several specific cytokine inhibitors now in development for the treatment of asthma and other allergic diseases. The effects of inhibiting the T helper 2 cytokines interleukin-5, interleukin-13 and interleukin-9 are discussed, together with inhibition of tumor necrosis factor-alpha. Inhibitory cytokines, such as interleukin-10, interferons and interleukin-12, are also being considered in the treatment of allergic diseases.
CT and MR imaging of pancreatic cancer. (2001)

Recent improvements in imaging techniques have made it possible to improve the diagnostic accuracy for detection, staging, and indicating surgical resectability of pancreatic cancer. The latest advance in the computed tomography technique, is the introduction of subsecond multislice helical scanning that improves z-axis resolution in the reformatted images and three-dimensional rendering with a large volume data. Magnetic resonance imaging provides versatile information including magnetic resonance cholangiopancreatography that allows noninvasive delineation of the pancreatic and biliary duct systems. The presence of pancreatic cancer may best be evaluated by dynamic computed tomography or dynamic magnetic resonance imaging with administration of intravenous contrast material. Both computed tomography and magnetic resonance imaging are valuable for the preoperative assessment of local invasion and vascular involvement. Multislice helical computed tomography is currently considered as the best single modality for the diagnosis of pancreatic cancer as it provides excellent image quality. When advanced magnetic resonance imaging equipment is used as a primary modality, in the future, it may have a possibility to replace other imaging modalities.
Proper processing of dengue virus nonstructural glycoprotein NS1 requires the N-terminal hydrophobic signal sequence and the downstream nonstructural protein NS2a (1989)

Expression of dengue virus gene products involves specific proteolytic cleavages of a precursor polyprotein. To study the flanking sequences required for expression of the dengue virus nonstructural glycoprotein NS1, we constructed a series of recombinant vaccinia viruses that contain the coding sequence for NS1 in combination with various lengths of upstream and downstream sequences. The NS1 products expressed by these viruses in infected CV-1 cells were immune precipitated and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The data show that the 24-residue hydrophobic sequence preceding NS1 was necessary and sufficient for the production of glycosylated NS1 and that this sequence was cleaved from NS1 in the absence of most dengue virus proteins. This finding is consistent with previous proposals that this hydrophobic sequence serves as an N-terminal signal sequence that is cleaved by signal peptidase. The cleavage between the C terminus of NS1 and the downstream protein NS2a occurred when the complete NS2a was present. Recombinant viruses containing NS1 plus 15 or 49% of NS2a produced proteins larger than authentic NS1, indicating that the cleavage between NS1 and NS2a had not occurred. Failure of cleavage was not corrected by coinfection with a recombinant virus capable of cleavage. These results suggest that NS2a may be a cis-acting protease that cleaves itself from NS1, or NS2a may provide sequences for recognition by a specific cellular protease that cleaves at the NS1-NS2a junction.
Association betweenCampylobacterInfection and Guillain‐Barré Syndrome (1997)

Guillain-Barré syndrome (GBS), a neurologic disease that produces ascending paralysis, affects people all over the world. Acute infectious illnesses precede 50%-75% of the GBS cases. Although many infectious agents have been associated with GBS, the strongest documented association is with Campylobacter infection. The first line of evidence supporting Campylobacter infection as a trigger of GBS is anecdotal reports. The second line of evidence is serologic surveys, which have demonstrated that sera from GBS patients contain anti-Campylobacter jejuni antibodies, consistent with recent infection. Finally, culture studies have proven that a high proportion of GBS patients have C. jejuni in their stools at the time of onset of neurologic symptoms. Neurologic symptoms are more severe and more likely to be irreversible when GBS is preceded by C. jejuni infection. One of every 1058 Campylobacter infections results in GBS, and 1 of 158 Campylobacter type O:19 infections results in GBS.
Management of digoxin toxicity (2016)

Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur even when the serum digoxin concentration is within the therapeutic range. Toxicity causes anorexia, nausea, vomiting and neurological symptoms. It can also trigger fatal arrhythmias. There is a range of indications for using digoxin-specific antibody fragments. The amount ingested and serum digoxin concentration help to determine the dose required, but are not essential. Digoxin-specific antibody fragments are safe and effective in severe toxicity. Monitoring should continue after treatment because of the small risk of rebound toxicity. Restarting therapy should take into account the indication for digoxin and any reasons why the concentration became toxic.
Precise and Heritable Genome Editing in Evolutionarily Diverse Nematodes Using TALENs and CRISPR/Cas9 to Engineer Insertions and Deletions (2013)

Exploitation of custom-designed nucleases to induce DNA double-strand breaks (DSBs) at genomic locations of choice has transformed our ability to edit genomes, regardless of their complexity. DSBs can trigger either error-prone repair pathways that induce random mutations at the break sites or precise homology-directed repair pathways that generate specific insertions or deletions guided by exogenously supplied DNA. Prior editing strategies using site-specific nucleases to modify the Caenorhabditis elegans genome achieved only the heritable disruption of endogenous loci through random mutagenesis by error-prone repair. Here we report highly effective strategies using TALE nucleases and RNA-guided CRISPR/Cas9 nucleases to induce error-prone repair and homology-directed repair to create heritable, precise insertion, deletion, or substitution of specific DNA sequences at targeted endogenous loci. Our robust strategies are effective across nematode species diverged by 300 million years, including necromenic nematodes (Pristionchus pacificus), male/female species (Caenorhabditis species 9), and hermaphroditic species (C. elegans). Thus, genome-editing tools now exist to transform nonmodel nematode species into genetically tractable model organisms. We demonstrate the utility of our broadly applicable genome-editing strategies by creating reagents generally useful to the nematode community and reagents specifically designed to explore the mechanism and evolution of X chromosome dosage compensation. By developing an efficient pipeline involving germline injection of nuclease mRNAs and single-stranded DNA templates, we engineered precise, heritable nucleotide changes both close to and far from DSBs to gain or lose genetic function, to tag proteins made from endogenous genes, and to excise entire loci through targeted FLP-FRT recombination.
Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824 (2004)

We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48-72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G(2)-M phase of the cell cycle after compound treatment. However, an increased sub-G(1) population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.
The low-toxicity versions of LPS, MPL® adjuvant and RC529, are efficient adjuvants for CD4+ T cells (2005)

Lipopolysaccharide (LPS) has long been known to enhance innate and adaptive immune responses; however, its extreme toxicity precludes its use in clinical settings. The combined toxicity and adjuvanticity of LPS have contributed to the view that immunological adjuvants need to be highly inflammatory to be maximally effective. Here, we compared the effects of LPS with its less-toxic derivatives, monophosphoryl lipid A (MPL) and a chemical mimetic, RC529, on CD4+ T cell clonal expansion, long-term survival, and T helper cell type 1 (Th1) differentiation. We found that LPS, MPL, and RC529 had similar effects on CD4+ T cell clonal expansion, cell division, and ex vivo survival. Analysis of the ability of activated CD4+ T cells to produce interferon-gamma following a 21-day immunization and challenge protocol with LPS and MPL resulted in similar Th1 differentiation. In contrast, we found that LPS was more effective in promoting long-term CD4+ T cell responses, as we recovered nearly sixfold more cells following immunization/challenge as compared with treatment with MPL. Our results indicate that low-inflammation adjuvants, such as MPL and RC529, are capable of enhancing short-term CD4+ T cell clonal expansion and Th1 differentiation, but inflammatory signaling aids in the long-term retention of antigen-specific T cells.
The first influenza pandemic of the new millennium (2011)

In the spring of 2009, a novel influenza A virus of the H1N1 subtype emerged that transmitted efficiently among humans; by June of 2009, the outbreak reached pandemic status. The pandemic virus possesses six viral RNA segments from so-called triple reassortant swine viruses that emerged in North American pig populations in the late 1990s and two viral RNA segments from Eurasian avian-like swine influenza viruses. Most human infections with the virus have been mild; however, severe and fatal infections occurred among certain risk groups, but also among those without any known risk factors. Here, we summarize the evolutionary, epidemiological, clinical, and molecular findings on the pandemic virus. We also discuss the arsenal of antiviral compounds and vaccines available to prevent and treat infections with the virus.
Innovations in integrated assessment: The tracking and analysis framework (TAF) (1997)

The Clean Air Act Amendments of 1990 introduced innovation in environmental regulation by legislating trading in emissions allowances. The Tracking and Analysis Framework (TAF) is an integrated model for assessment designed to provide a comprehensive understanding of the economic and environmental effects of this legislation. TAF provides a general framework which links together a set of modules that project reductions in emissions of sulfur and nitrogen oxides, control costs, atmospheric transport, ambient pollutant concentrations and deposition, their environmental effects on visibility, aquatic ecosystems, soils, and human health, and the economic valuation of these effects. The goal of TAF is to integrate credible models of the science and technology into an assessment framework that can directly address key policy issues, and in doing so act as a bridge between science and policy. Key objectives of TAF include comprehensive coverage, agility and flexibility, transparency, scientific credibility, and explicit treatment of uncertainty. TAF achieves these objectives by an innovative combination of methods, including influence diagrams, hierarchical modules, integrated documentation, reduced-form models, probabilistic uncertainty analysis, distributed development, and progressive refinement. This paper and its companions describes the methods used, details on selected modules, and initial results.