gebhart/patrepeval huggingface dataset:
Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase (1993)

A number of chemically distinct nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been reported. Several lines of evidence, including the isolation of RT mutants that show cross resistance, suggest that, despite their structural diversity, many of these inhibitors bind to a common site on HIV-1 RT. We have recently reported that, on the basis of analyses of HIV-1/HIV-2 chimeras, the natural product calanolide A may interact with a different site or sites in HIV-1 RT. We have used BspMI cassette mutagenesis to prepare a collection of HIV-1 RT mutants that show resistance to the known members of the general class of nonnucleoside inhibitors. This collection of mutants can be used to determine whether a new drug will show cross resistance with known inhibitors and to define amino acid positions critical for the action of the drugs. The mutants were used to analyze calanolide A, 1H,3H-thiazolo[3,4-a]benzimidazole(4i), and the acyclic nucleoside analog 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. These analyses suggest that all three drugs interact with HIV-1 RT within the previously defined common binding site for nonnucleoside inhibitors. However, the drugs respond differently to the panel of drug-resistant HIV-1 RTs, indicating that while the binding sites of the drugs overlap they are not identical.
Control of HPV-associated tumors by innovative therapeutic HPV DNA vaccine in the absence of CD4+ T cells (2014)

Human papillomavirus (HPV) infections are particularly problematic for HIV + and solid organ transplant patients with compromised CD4+ T cell-dependent immunity as they produce more severe and progressive disease compared to healthy individuals. There are no specific treatments for chronic HPV infection, resulting in an urgent unmet need for a modality that is safe and effective for both immunocompromised and otherwise normal patients with recalcitrant disease. DNA vaccination is attractive because it avoids the risks of administration of live vectors to immunocompromised patients, and can induce potent HPV-specific cytotoxic T cell responses. We have developed a DNA vaccine (pNGVL4a-hCRTE6E7L2) encoding calreticulin (CRT) fused to E6, E7 and L2 proteins of HPV-16, the genotype associated with approximately 90% vaginal, vulvar, anal, penile and oropharyngeal HPV-associated cancers and the majority of cervical cancers. Administration of the DNA vaccine by intramuscular (IM) injection followed by electroporation induced significantly greater HPV-specific immune responses compared to IM injection alone or mixed with alum. Furthermore, pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation of mice carrying an intravaginal HPV-16 E6/E7-expressing syngeneic tumor demonstrated more potent therapeutic effects than IM vaccination alone. Of note, administration of the DNA vaccine by IM injection followed by electroporation elicited potent E6 and E7-specific CD8+ T cell responses and antitumor effects despite CD4+ T cell-depletion, although no antibody response was detected. While CD4+ T cell-depletion did reduce the E6 and E7-specific CD8+ T cell response, it remained sufficient to prevent subcutaneous tumor growth and to eliminate circulating tumor cells in a model of metastatic HPV-16+ cancer. Thus, the antibody response was CD4-dependent, whereas CD4+ T cell help enhanced the E6/E7-specific CD8+ T cell immunity, but was not required. Taken together, our data suggest that pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation warrants testing in otherwise healthy patients and those with compromised CD4+ T cell immunity to treat HPV-16-associated anogenital disease and cancer.
Tumor-Specific Targeting of Pancreatic Cancer with Shiga Toxin B-Subunit (2011)

Pancreatic carcinoma is one of the most aggressive tumor entities, and standard chemotherapy provides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb(3) or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb(3) in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n = 27). The mean expression was highly significantly increased from 30 ± 16 ng Gb(3)/mg tissue in normal pancreas to 61 ± 41 ng Gb(3)/mg tissue (mean ± SD, P = 0.0006), as evidenced by thin layer chromatography. Upregulation of Gb(3) levels did not depend on tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb(3) expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lines was increased more than 100-fold compared with irinotecan. Moreover, this effect was effectively blocked by competing incubation with nonlabeled STxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer.
Tacrolimus (FK506) in the treatment of severe, refractory rheumatoid arthritis: initial experience in 12 patients. (1999)

Tacrolimus was tolerated by only 7 of 12 patients, but in 5 of these 7 patients with severe and refractory disease, the clinical responses were very good.
EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: a meta-analysis (2012)

Although increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.
The Pathophysiology of Acquired Aplastic Anemia (1997)

Plastic anemia, which is pancytopenia with a fatty or “empty” bone marrow, is remarkable for the simplicity of its pathologic picture and the direct derivation of its clinical manifestations.1 Although it is not a common disease, the drama of an individual case and the larger consequences of its associations give it considerable interest. That aplastic anemia is perhaps the most dreaded idiosyncratic complication of drug treatment has serious and often expensive consequences for drug development, for risk assessment, for approval by regulatory agencies, and in legal actions.Aplastic anemia, first described by Paul Ehrlich in 1888 from an autopsy of . . .
2-Cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor in colon and pancreatic cancer cells (2007)

Betulinic acid (BA) is a phytochemical triterpenoid acid from bark extracts and is cytotoxic to cancer cells and tumors. We modified the A-ring of BA to give a 2-cyano-1-en-3-one moiety and the effects of the 2-cyano-lup-1-en-3-oxo-20-oic acid (CN-BA), 2-cyano derivative of BA, and its methyl ester (CN-BA-Me) were investigated in colon and pancreatic cancer cells. Both CN-BA and CN-BA-Me were highly cytotoxic to Panc-28 pancreatic and SW480 colon cancer cells. CN-BA and CN-BA-Me also induced differentiation in 3T3-L1 adipocytes, which exhibited a characteristic fat droplet accumulation induced by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Based on these results, we investigated the activities of CN-BA and CN-BA-Me as PPARgamma agonists using several receptor-mediated responses including activation of transfected PPARgamma-responsive constructs, induction of p21 in Panc-28 cells and induction of caveolin-1 and Krüppel-like factor 4 in colon cancer cells. The results clearly demonstrated that both CN-BA and CN-BA-Me activated PPARgamma-dependent responses in colon (caveolin-1) and pancreatic (p21) cancer cells, whereas induction of KLF4 by these compounds in colon cancer cells was PPARgamma independent and also dependent on cell context. The PPARgamma agonist activities of CN-BA and CN-BA-Me were structure-, response/gene- and cell context-dependent suggesting that these compounds are a novel class of selective PPARgamma modulators with potential for clinical treatment of colon and pancreatic cancer.
A turning point in proteome analysis: Sample prefractionationvia multicompartment electrolyzers with isoelectric membranes (2000)

Sample prefractionation, as obtained via multicompartment electrolyzers with isoelectric membranes, greatly enhanced the load ability, resolution and detection sensitivity of two-dimensional (2-D) maps in proteome analysis. This was demonstrated with different samples. In an Escherichia coli total cell extract, analysis by a 2-D map run in a pH 4-5 gradient showed many more spots when prefractionated, as compared with standard maps available in databases such as SWISS-2DPAGE. Analysis of human plasma in the pH 3-6 range showed an increase in the number of highly acidic proteins in the fractionated sample compared to whole plasma. With both samples no protein precipitation or smears occurred and much larger sample amounts could be loaded upon prefractionation, so that a large number of spots could be visualized by Coomassie staining, which is fully compatible with subsequent matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) analysis.
Aminoacyl-tRNA synthetase complexes: molecular multitasking revealed (2008)

The accurate synthesis of proteins, dictated by the corresponding nucleotide sequence encoded in mRNA, is essential for cell growth and survival. Central to this process are the aminoacyl-tRNA synthetases (aaRSs), which provide amino acid substrates for the growing polypeptide chain in the form of aminoacyl-tRNAs. The aaRSs are essential for coupling the correct amino acid and tRNA molecules, but are also known to associate in higher order complexes with proteins involved in processes beyond translation. Multiprotein complexes containing aaRSs are found in all three domains of life playing roles in splicing, apoptosis, viral assembly, and regulation of transcription and translation. An overview of the complexes aaRSs form in all domains of life is presented, demonstrating the extensive network of connections between the translational machinery and cellular components involved in a myriad of essential processes beyond protein synthesis.
SH3 domains of the adapter molecule Grb2 complex with two proteins in T cells: the guanine nucleotide exchange protein Sos and a 75-kDa protein that is a substrate for T cell antigen receptor-activated tyrosine kinases. (1994)

In T lymphocytes activated via the T cell antigen receptor (TCR), the SH2- and SH3-containing adapter molecule Grb2 forms a complex with the Ras guanine nucleotide exchange protein Sos and tyrosine phospho-proteins. The interaction of Sos with Grb2 is mediated via the Grb2 SH3 domains. In this study, it is shown that a 75-kDa protein is also complexed with the Grb2 SH3 domains in T cells, but not in Rat-1 fibroblasts. The identity of the p75 protein is not known, but immunoblot analysis with phosphotyrosine antibodies indicated that it is rapidly tyrosine-phosphorylated in TCR-activated T cells. This characteristic clearly distinguishes p75 from Sos since Sos is not a phosphotyrosine protein. In vitro binding studies indicated that the p75 phosphotyrosine protein binds to a glutathione S-transferase fusion protein of intact Grb2, but not to a Grb2 fusion protein mutated in its SH3 domains. p75 can also bind to the single COOH-terminal Grb2 SH3 domain, whereas Sos has an in vitro binding preference for the NH2-terminal Grb2 SH3 domain. Collectively, these data indicate that in T cells, two proteins can complex with the Grb2 SH3 domains: Sos and a p75 molecule that is tyrosine-phosphorylated in TCR-activated cells. The significance of p75 association with Grb2 is not clear, but by analogy with Sos, p75 is a potential candidate for a Grb2 effector protein. Data are presented showing that the interaction of the Grb2 SH2 domains with tyrosine phosphoproteins may be regulated by conformational restraints imposed by different molecules complexing with the Grb2 SH3 domains. It is thus possible to speculate that the interaction of either p75 or Sos with the Grb2 SH3 domain may influence the interaction of the Grb2 SH2 domain with tyrosine phosphoproteins.
Thermal stability of polyethylene terephthalate (PET): oligomer distribution and formation of volatiles (1999)

Two ovenable PET (polyethylene terephthalate) samples were investigated under severe heating conditions and oligomers and volatile substances were analysed as potential migrants into foods. The samples were tested for migration into water, 3% acetic acid and 15% ethanol solution for 1 hour at 95°C. Overall migration and the specific migration of terephthalic acid, ethylene glycol and diethylene glycol were all very low. The plastics were heated at 150°C, 260°C and 270°C, for 5 minutes 30 minutes and 60 minutes. Oligomer analysis by LC/MS (liquid chromatography-MS) showed that the concentration of the second series alicyclic oligomers increased up to 15-fold on heating whereas the major oligomer fraction, the cyclic trimer, tetramer, pentamer and hexamer showed only minor concentration changes with heating. Volatiles evolved by the samples were trapped on a Tenax trap and identified by GC/MS (gas chromatography-MS). They were few in number and low in concentration and none merited migration tests. It is concluded that even when tested up to melting point, PET plastics of this type have good temperature stability and are well suited for high-temperature food contact applications. Copyright © 1999 John Wiley & Sons, Ltd.
Microwave and millimeter-wave high-Q micromachined resonators (1999)

Alternative techniques for integrating high-quality factor resonators using micromachining techniques have been investigated. Two methods are presented which include suspending microstrip lines on thin dielectric membranes, resulting in an effective dielectric constant of near unity, and integrating three-dimensional micromachined waveguide cavity resonators with planar feedlines. These resonators show large improvements in quality factor over conventional techniques, and more importantly, allow for planar integration in complex systems. Resonators were fabricated in suspended microstrip at 29, 37, and 62 GHz with quality factors of over 450 with very close agreement between simulated and measured results. An integrated micromachined cavity resonator was also fabricated with a TE011 resonance quality factor of 1117 at 24 GHz and a TE021 resonance quality factor of 1163 at 38 GHz. To the authors' knowledge, these are the highest quality factor planar resonators without the use of superconductive materials, and can be used in microwave and millimeter-wave low-loss filters and low-phase-noise oscillators. ©1999 John Wiley & Sons, Inc. Int J RF and Microwave CAE 9: 326–337, 1999.
Thalidomide Inhibits Tumor Necrosis Factor-α-Induced Interleukin-8 Expression in Endometriotic Stromal Cells, Possibly through Suppression of Nuclear Factor-κB Activation (2005)

The current study showed for the first time that Thal treatment attenuated the expression of IL-8 by reducing TNF-alpha-induced NF-kappaB activation.
Neural networks and fuzzy systems: a dynamical systems approach to machine intelligence (1991)

This work combines neural networks and fuzzy systems, presenting neural networks as trainable dynamical systems and developing mechanisms and principles of adaption, self-organization, convergence and global stability. It includes the new geometric theory of fuzzy sets, systems and associated memories, and shows how to apply fuzzy set theory to adaptive control and how to generate structured fuzzy systems with unsupervised neural techniques.
The protease-antiprotease battle in the cystic fibrosis lung (1999)

It is well recognized that long-standing inflammation damages the lungs in children and adults with cystic fibrosis (CF), and it is no coincidence that most CF deaths are due to respiratory failure. The lung inflammation is primarily due to the host response to chronic bacterial infection, particularly with Pseudomonas aeruginosa, which calls into question the whole concept of colonization, with its implication of bacteria residing harmlessly in the body. However, it has also been suggested that inflammation may actually precede microbial infection in the CF lung, an idea based on the fact that significant inflammation has been detected in broncho-alveolar lavage (BAL) samples in which microbes (bacteria, viruses or fungi) were not isolatedl2. It is possible that in the young patients studied the infection had been eradicated but that the resultant inflammation simply persisted3. In older children, however, it is unlikely that the pathogenic bacteria are ever eradicated. In addition, using more sensitive molecular techniques for identifying bacteria, it may be that infection is going unrecognized when standard culture methods are employed4. More recently, it has been suggested that inflammation may be an integral part of the CF defect. Accumulation of faulty CFTR (CF transmembrane conductance regulator) protein in the cell endoplasmic reticulum may result in production of proinflammatory cytokines following activation of the transcription factor NFKB5. In conclusion, it seems most likely that the majority of lung inflammation is in fact secondary to recurrent bacterial or viral infections, but that there is a contribution from endogenous factors, and possibly even a reaction to the abnormal mucus lining the epithelium. It is still unexplained why the production of interleukin-10, an important anti-inflammatory cytokine, is reduced in CF epithelial cells67.
Type II-C CRISPR-Cas9 Biology, Mechanism, and Application (2017)

Genome editing technologies have been revolutionized by the discovery of prokaryotic RNA-guided defense system called CRISPR-Cas. Cas9, a single effector protein found in type II CRISPR systems, has been at the heart of this genome editing revolution. Nearly half of the Cas9s discovered so far belong to the type II-C subtype but have not been explored extensively. Type II-C CRISPR-Cas systems are the simplest of the type II systems, employing only three Cas proteins. Cas9s are central players in type II-C systems since they function in multiple steps of the CRISPR pathway, including adaptation and interference. Type II-C CRISPR systems are found in bacteria and archaea from very diverse environments, resulting in Cas9s with unique and potentially useful properties. Certain type II-C Cas9s possess unusually long PAMs, function in unique conditions (e.g., elevated temperature), and tend to be smaller in size. Here, we review the biology, mechanism, and applications of the type II-C CRISPR systems with particular emphasis on their Cas9s.
Ion Release Kinetics and Particle Persistence in Aqueous Nano-Silver Colloids (2010)

Many important aspects of nanosilver behavior are influenced by the ionic activity associated with the particle suspension, including antibacterial potency, eukaryotic toxicity, environmental release, and particle persistence.The present study synthesizes pure, ion-free, citrate-stabilized nanosilver (nAg) colloids as model systems, and measures their time-dependent release of dissolved silver using centrifugal ultrafiltration and atomic absorption spectroscopy. Ion release is shown to be a cooperative oxidation process requiring both dissolved dioxygen and protons. It produces peroxide intermediates, and proceeds to complete reactive dissolution under some conditions. Ion release rates increase with temperature in the range 0-37 °C, and decrease with increasing pH or addition of humic or fulvic acids. Sea salts have only a minor effect on dissolved silver release. Silver nanoparticle surfaces can adsorb Ag(+), so even simple colloids contain three forms of silver: Ag(0) solids, free Ag(+) or its complexes, and surface-adsorbed Ag(+). Both thermodynamic analysis and kinetic measurements indicate that Ag(0) nanoparticles will not be persistent in realistic environmental compartments containing dissolved oxygen. An empirical kinetic law is proposed that reproduces the observed effects of dissolution time, pH, humic/fulvic acid content, and temperature observed here in the low range of nanosilver concentration most relevant for the environment.
High-Density Labeling of DNA for Single Molecule Sequencing (2004)

Two unusual enzymatic activities are required for the realization of a single molecule sequencing: a polymerase for copying a deoxyribonuclease (DNA) target into complementary flurophore-labeled DNA, and an exonuclease for the successive hydrolysis of the completely dye-labeled DNA. Recently, we found that the wild-type Klenow fragment of Escherichia coli DNA polymerase I is well-suited for the synthesis of DNA in a reaction set-up that contains exclusively specific rhodamine-labeled analogs of the natural pyrimidine nucleotides (dCTP and dTTP). This protocol describes the procedure used for the preparation of DNA that is labeled at all pyrimidine bases of one strand, as well as an example of enzymatic downstream processing of the DNA product.
Plenoptic image editing (2002)

This paper presents a new class of interactive image editing operations designed to maintain consistency between multiple images of a physical 3D scene. The distinguishing feature of these operations is that edits to any one image propagate automatically to all other images as if the (unknown) 3D scene had itself been modified. The modified scene can then be viewed interactively from any other camera viewpoint and under different scene illuminations. The approach is useful first as a power-assist that enables a user to quickly modify many images by editing just a few, and second as a means for constructing and editing image-based scene representations by manipulating a set of photographs. The approach works by extending operations like image painting, scissoring, and morphing so that they alter a scene's generalized plenoptic function in a physically-consistent way, thereby affecting scene appearance from all viewpoints simultaneously. A key element in realizing these operations is a new volumetric decomposition technique for reconstructing an scene's plenoptic function from an incomplete set of camera viewpoints.
Effects of Essential Amino Acid Supplementation on Muscular Adaptations to 3 Weeks of Combined Unilateral Glenohumeral & Radiohumeral Joints Immobilisation (2013)

Effects of Essential Amino Acid Supplementation on Muscular Adaptations to 3 Weeks of Combined Unilateral Glenohumeral & Radiohumeral Joints Immobilisation Short-term immobilisation results in a decrease in muscle size and strength. Ingestion of essential amino-acids (EAAs) stimulates net protein synthesis and supplementation is shown to improve lean body mass, strength and physical function, even without exercise. This study set out to determine whether EAA supplementation would attenuate immobilisation-induced changes in muscle characteristics.We conclude that EAA supplementation impacts positively on the immobilisation-induced changes in the structural and functional characteristic of the remaining muscle. Our findings are relevant to both sporting (e.g. off-season detraining