gebhart/patrepeval huggingface dataset:
Use of a gp120 Binding Assay To Dissect the Requirements and Kinetics of Human Immunodeficiency Virus Fusion Events (1999)

Binding of the extracellular subunit of human immunodeficiency type 1 (HIV-1) envelope (Env) glycoprotein (gp120) to CD4 triggers the induction or exposure of a highly conserved coreceptor binding site in gp120 that helps mediate membrane fusion. Characterizing the structural features involved in gp120-coreceptor binding and the conditions under which binding occurs is important for understanding the fusion process, the evolution of pathogenic strains in vivo, the identification of novel anti-HIV compounds, and the development of HIV vaccines that utilize triggered structures of Env. Here we use the kinetics of interaction between CCR5 and gp120 to understand temporal and structural changes that occur during viral fusion. Using saturation binding and homologous competition analysis, we estimated the K(d) of interaction between CCR5 and gp120 from the macrophage tropic HIV-1 strain JRFL to be 4 nM. Unlike Env-mediated fusion, gp120 binding to CCR5 did not require divalent cations or elevated temperatures. Binding was not significantly affected by the pH of binding, G-protein coupling of CCR5, or partial gp120 deglycosylation. Oligomeric, uncleaved JRFL gp140 failed to bind CCR5 despite its ability to bind CD4 and monoclonal antibody 17b, suggesting that the uncleaved ectodomain of gp41 interferes with full exposure of the chemokine receptor binding site. Exposure of the chemokine receptor binding site on gp120 could be induced rapidly by CD4, but exposure of this site was lost upon CD4 dissociation from gp120, indicating that the conformational changes in gp120 induced by CD4 binding are fully reversible. The functional gp120-soluble CD4 complex was remarkably stable over time and temperature ranges, offering the possibility that complexes in which the highly conserved coreceptor binding site in gp120 is exposed can be used for vaccine development.
Molecular imaging of Cathepsin E-positive tumors in mice using a novel protease-activatable fluorescent probe (2011)

The small animal studies demonstrated the capability of probe a for imaging Cath E-positive tumors. The developed optical probe could be applied in early diagnostic imaging and guiding subsequent surgical procedure.
Ketamine: An Introduction for the Painand Palliative Medicine Physician (2007)

A history of an escalating chronic intractable pain in a patient with cryoglobulinemia, vasculitis, and severe cutaneous ulcerations is presented. A strategy of progressive, multi-agent, N-methyl-D-aspartate-receptor (NMDA-R) blockade that resulted in adequate pain control and a three-fold reduction in opioid consumption is described. Diagnostic process of neuropathic pain and the role of NMDA-R in the development of hyperalgesia are briefly reviewed. Thereafter, existing clinical literature describing the use of Ketamine, a major NMDA-R antagonist for management of malignant pain, is reviewed. Lastly, evidence-based original protocol for intravenous adjuvant Ketamine analgesia for severe cancer pain is presented.
Lubiprostone for Opioid‐Induced Constipation Does Not Interfere with Opioid Analgesia in Patients with Chronic Noncancer Pain (2016)

Lubiprostone 24 μg BID administered for relief of OIC in patients with chronic noncancer pain does not interfere with opioid analgesia.
CD8 T cell response in a phase I study of therapeutic vaccination of advanced NSCLC with allogeneic tumor cells secreting endoplasmic reticulum-chaperone gp96-Ig-peptide complexes (2013)

Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.
Focus dependent multi-level graph clustering (2004)

In this paper we propose a structure-based clustering technique that transforms a given graph into a specific double tree structure called multi-level outline tree. Each meta-node of the tree - that represents a subset of nodes - is itself hierarchically clustered. So, a meta-node is considered as a tree root of included clusters.The main originality of our approach is to account for the user focus in the clustering process to provide views from different perspectives. Multi-level outline trees are computed in linear time and easy to explore. We think that our technique is well suited to investigate various graphs like Web graphs or citation graphs.
Expression of Neuronal Markers in Differentiated Marrow Stromal Cells and CD133+ Stem-Like Cells (2003)

Bone marrow stromal cells, which normally give rise to bone, cartilage, adipose tissue, and hematopoiesis-supporting cells, have been shown to differentiate in vitro and in vivo into neural-like cells. In this study, we examined the expression of neuronal and glial markers in human marrow stromal cells under culture conditions appropriate for neural stem cells, and compared the unsorted cell population to bone marrow CD133+ stem-like cells using immunofluorescence, Western blot, and functional patch-clamp analysis. Overall, the expression of the early neuronal marker beta3-tubulin was most pronounced in the presence of DMEM/F12 and neurotrophin 3 (NT3) or brain-derived neurotrophic factor (BDNF), when marrow stromal cells were cultured onto fibronectin. Electrophysiological examination, however, could not show fast sodium currents or functional neurotransmitter receptors in differentiated marrow stromal cells. CD133+ mesenchymal stem-like cells, but not CD34+/CD133- cells, generally showed a higher expression of neuronal markers than did unsorted marrow stromal cells, and differentiated CD133+ cells more resembled neuron-like cells.
Massively-parallel vector graphics (2014)

We present a massively parallel vector graphics rendering pipeline that is divided into two components. The preprocessing component builds a novel adaptive acceleration data structure, the shortcut tree . Tree construction is efficient and parallel at the segment level, enabling dynamic vector graphics. The tree allows efficient random access to the color of individual samples, so the graphics can be warped for special effects. The rendering component processes all samples and pixels in parallel. It was optimized for wide antialiasing filters and a large number of samples per pixel to generate sharp, noise-free images. Our sample scheduler allows pixels with overlapping antialiasing filters to share samples. It groups together samples that can be computed with the same vector operations using little memory or bandwidth. The pipeline is feature-rich, supporting multiple layers of filled paths, each defined by curved outlines (with linear, rational quadratic, and integral cubic Bézier segments), clipped against other paths, and painted with semi-transparent colors, gradients, or textures. We demonstrate renderings of complex vector graphics in state-of-the-art quality and performance. Finally, we provide full source-code for our implementation as well as the input data used in the paper.
Structural Insights into the Protein Splicing Mechanism of PI-SceI (2000)

PI-SceI is a member of a class of proteins (inteins) that excise themselves from a precursor protein and in the process ligate the flanking protein sequences (exteins). We report here the 2.1-A resolution crystal structure of a PI-SceI miniprecursor (VMA29) containing 10 N-terminal extein residues and 4 C-terminal extein residues. Mutations at the N- and C-terminal splicing junctions, blocking in vivo protein splicing, allowed the miniprecursor to be purified and crystallized. The structure reveals both the N- and C-terminal scissile peptide bonds to be in distorted trans conformations (tau approximately 100 degrees ). Modeling of the wild-type PI-SceI based on the VMA29 structure indicates a large conformational change (movement of >9 A) must occur to allow transesterification to be completed. A zinc atom was discovered at the C-terminal splicing junction. Residues Cys(455), His(453), and Glu(80) along with a water molecule (Wat(53)) chelate the zinc atom. The crystal structure of VMA29 has captured the intein in its pre-spliced state.
Physiology and pathophysiology of nitric oxide in the nervous system, with special mention of the islands of Calleja and the circunventricular organs. (2002)

Nitric oxide (NO) has been recognized as a key regulatory factor in many physiological processes, including central nervous system function, development, and phatophysiology. NO is produced by a class of enzymes known as NO synthases (NOS) and in normal adult animals only the neuronal isoform (nNOS) is detectable. During cortical development, nNOS was found at E14 in neuroblasts of the marginal zone and its expression raised to a zenith by P5, decreasing afterwards until reaching a steady level by P10. At that time, nNOS was found mainly in pyramidal neurons. Interestingly, the inducible isoform of the enzyme (iNOS) was also active from P3 to P7, but it disappeared almost completely by P20. The neurodegeneration observed during normal aging and following hypoxic accidents seems to be the result of cumulative free radical damage, and excessive production of NO may be at the basis of the cascade. After ischemic events we observed an elevation in the number of neurons expressing nNOS coincident with an elevation in Ca2+-dependent NOS activity for up to 120 min. After this period, nNOS activity began to decrease but it was substituted by a rapid increase in Ca2+-independent activity coincident with the histological appearance of previously undetectable iNOS-immunoreactive neurons. These increases in NO production were accompanied by specific patterns of protein nitration, a process that seems to result in loss of protein function. In particular, we observed a correlation between exposure to ischemia-reperfusion and nitration of cytochrome c. This process was coincident with the exit of the cytochrome from the mitochondria to the surrounding cytoplasm, an early event in neuronal apoptosis. Interestingly, most of the morphological and molecular changes associated with ischemic damage were prevented by treatment with inhibitors of NO production, indicating a clear path in the search for efficacious drugs in the battle against cerebrovascular accidents.
A new technique for measuring retrograde vitrification in polymer-gas systems and for making ultramicrocellular foams from the retrograde phase (2000)

A stepwise temperature- and pressure-scanning thermal analysis method was developed to measure glass-transition temperature Tg in the two-phase polymer–gas systems as a function of gas pressure p, and was used to confirm recent theoretical predictions that certain polymer–gas systems exhibit retrograde vitrification, that is, they undergo rubber-to-glass transition on heating. A complete Tg-p profile delineating the glass–rubber phase envelope was established for the PMMA-CO2 system. The retrograde vitrification behavior observed, where at certain gas pressures the polymer exists in the rubbery state at low and high temperatures and in the glassy state at intermediate temperatures, was similar to that reported previously based on the creep-compliance measurements. The existence of the rubbery state at low temperatures was used to generate foams by saturating the polymer with CO2 at 34 atm and at temperatures in the range −0.2 to 24 °C followed by foaming at temperatures in the range 24 to 90 °C. Foams with very fine cell structure never reported before could be prepared by this technique. For example, PMMA foams with average cell size of 0.35 μm and cell density of 4.4 × 1013 cells/g were prepared by processing the low temperature rubbery phase. © 2000 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 38: 716–725, 2000
Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. (1995)

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that can be transferred to naive mice via CD4+ T cells isolated from appropriately immunized mice. We have evaluated the effects of recombinant murine interleukin 12 (rmIL-12), a potent inducer of interferon gamma (IFN-gamma) and promoter of Th1 T cell development, on the course of adoptively transferred EAE. The transfer of lymph node cells (LNC) isolated from proteolipid protein (PLP)-primed animals and stimulated in vitro with PLP to naive mice resulted in a progressive paralytic disease culminating in complete hind limb paralysis in the majority of the recipients. When mice were injected with LNC that had been stimulated in vitro with PLP in the presence of rmIL-12, the subsequent course of disease was more severe and prolonged. The addition of rmIL-12 during the in vitro stimulation with PLP resulted in a 10-fold increase in IFN-gamma and a 2-fold increase in tumor necrosis factor (TNF) alpha in the supernatants, relative to LNC stimulated with PLP alone. However, neutralization of IFN-gamma or TNF-alpha in vitro with specific antibodies did not abrogate the ability of rmIL-12 to exacerbate the subsequent disease. Similarly, mice treated with rmIL-12 in vivo after the transfer of antigen-stimulated LNC developed a more severe and prolonged course of disease compared with vehicle-treated control animals. In contrast, treatment of mice with an antibody to murine IL-12 after cell transfer completely prevented paralysis, with only 40% of the mice developing mild disease. These results demonstrate that in vitro stimulation of antigen primed LNC with PLP and rmIL-12 enhances their subsequent encephalitogenicity. Furthermore, inhibition of endogenous IL-12 in vivo after LNC transfer prevented paralysis, suggesting that endogenous IL-12 plays a pivotal role in the pathogenesis of this model of autoimmune disease.
Cloning, sequencing, and expression of the pantothenate kinase (coaA) gene of Escherichia coli (1992)

Pantothenate kinase catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis. The structural gene (coaA) located at 90 min of the Escherichia coli chromosome was cloned and sequenced. The coaA gene was transcribed in the opposite direction to the flanking genes birA and thrU and produced a single 1.1-kb transcript. Translation of the coaA gene produced two protein products (36.4 and 35.4 kDa) that differed by eight amino acids at the amino terminus. The poor homology of the coaA promoter region to consensus E. coli promoter sequences and the low frequency of optimal codon usage (0.565) were consistent with the low abundance of pantothenate kinase. Strains containing multiple copies of the coaA gene possessed 76-fold-higher specific activity of pantothenate kinase; however, there was only a 2.7-fold increase in the steady-state level of CoA. These data corroborate the conclusion that regulation of pantothenate kinase activity by feedback inhibition is the critical factor controlling the intracellular CoA concentration.
Natural killer cell engineering for cellular therapy of cancer (2011)

Natural killer (NK) cells can kill transformed cells and represent a promising tool for the treatment of cancer. Their function is governed by a balance of stimulatory and inhibitory signals triggered by surface receptors. Advances in NK cell therapy require the development of dependable methods for obtaining an adequate number of effector cells; additional activation or genetic modification may further increase their anticancer capacity. A method for NK cell expansion used in our laboratory relies on a genetically modified form of the K562 myeloid leukemia cell line, engineered to express a membrane-bound form of interleukin-15 and the ligand for the costimulatory molecule 4-1BB (CD137). Expanded NK cells can be transduced with genes encoding chimeric antigen receptors that stimulate tumor cell-specific cytotoxicity. These methods for NK cell expansion and genetic modification have been adapted to large-scale, clinical-grade, Current Good Manufacturing Practice conditions and support two active clinical trials. Summarized are current efforts for NK cell immunotherapy for cancer and future perspectives.
Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific protein. (1998)

These findings localize the basal promoter activity of RPE65, identify potential cis-acting elements that act as positive regulators of gene expression, and suggest that additional regulatory elements are likely to be involved in restricting gene expression to the retinal pigment epithelium. Identification of promoter elements and genetic markers in the upstream sequence will enable the screening of patients with retinal degeneration for possible mutations that affect RPE65 expression.
Hemophilia. Strategies for the treatment of inhibitor patients. (2000)

Symptomatic treatment of patients with hemophilia A and hemophilia B has now reached high levels of safety and efficacy. In consequence, at present the most prominent clinical complication is the development of inhibitors, which are alloantibodies directed against the coagulation factor demanded for substitution therapy in the management and prevention of bleeds. When de novo inhibitors are detected for the first time in a patient, several questions are raised. Since the clinical picture with inhibitors is dominated by an excessive tendency to bleed and reduced or lost efficacy of the usual factor concentrate, acute bleeding will often be a problem. Major questions from the patient and his next of kin are whether the inhibitors will disappear, and whether there is a therapy available that can cure this complication. Over the last 20-25 years, treatment programs have been established that seem to offer a reasonably good chance of suppressing inhibitors in hemophilia. Some protocols suggest the use of very high daily doses of factor VIII, whereas others propose much lower doses of factor VIII, seemingly with quite comparable rates of success. Therefore, controlled prospective clinical studies, focusing on the dosage aspect, are urgently required. Control of bleeding is another issue of great importance. In inhibitor patients with a low responder state, substitution with increased doses of factor VIII or IX may successfully arrest bleeding. In some hemophilia A patients with a high responder state, but with actual inhibitor titers in the lower range, a porcine factor VIII concentrate could be useful. In these cases the patient's anti-factor VIII antibody should display no major cross-reactivity towards the porcine factor VIII molecule. In patients with high-responder inhibitors, so-called bypassing agents may be used to control bleeding. There are two major classes of bypassing agents. Concentrates have been produced for more than two decades derived from plasma and characterized by a high content of vitamin K-dependent coagulation factors. Examples are the prothrombin complex concentrates (PCC), and the activated prothrombin complex concentrates (aPCC). A newly introduced recombinant activated factor VII molecule (rFVIIa) has gained approval in numerous countries based primarily on results from emergency use in a substantial number of individuals with inhibitors. Other, still experimental, products have been proposed, but no human clinical studies are available as of yet Inhibitors remain a challenge to patients and their physicians.
Diffuse intrinsic pontine glioma: poised for progress (2012)

Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.
De Novo Computational Design of Retro-Aldol Enzymes (2008)

The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model.