gebhart/patrepeval huggingface dataset:
The RgpB C-Terminal Domain Has a Role in Attachment of RgpB to the Outer Membrane and Belongs to a Novel C-Terminal-Domain Family Found in Porphyromonas gingivalis (2006)

Porphyromonas gingivalis produces outer membrane-attached proteins that include the virulence-associated proteinases RgpA and RgpB (Arg-gingipains) and Kgp (Lys-gingipain). We analyzed the P. gingivalis outer membrane proteome and identified numerous proteins with C-terminal domains similar in sequence to those of RgpB, RgpA, and Kgp, indicating that these domains may have a common function. Using RgpB as a model to investigate the role of the C-terminal domain, we expressed RgpB as a full-length zymogen (recombinant RgpB [rRgpB]), with a catalytic Cys244Ala mutation [rRgpB(C244A)], or with the C-terminal 72 amino acids deleted (rRgpB435) in an Arg-gingipain P. gingivalis mutant (YH522AB) and an Arg- and Lys-gingipain mutant (YH522KAB). rRgpB was catalytically active and located predominantly attached to the outer membrane of both background strains. rRgpB(C244A) was inactive and outer membrane attached, with a typical attachment profile for both background strains according to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but in YH522KAB, the prodomain was not removed. Thus, in vivo, RgpB export and membrane attachment are independent of the proteolytic activity of RgpA, RgpB, or Kgp. However, for maturation involving proteolytic processing of RgpB, the proteolytic activity of RgpB, RgpA, or Kgp is required. The C-terminally-truncated rRgpB435 was not attached to the outer membrane and was located as largely inactive, discrete 71-kDa and 48-kDa isoforms in the culture supernatant and the periplasm. These results suggest that the C-terminal domain is essential for outer membrane attachment and may be involved in a coordinated process of export and attachment to the cell surface.
Inhibitors of NF-κB and AP-1 Gene Expression:  SAR Studies on the Pyrimidine Portion of 2-Chloro-4-trifluoromethylpyrimidine-5-[N-(3‘,5‘-bis(trifluoromethyl)phenyl)carboxamide] (2000)

We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.
Feature Squeezing: Detecting Adversarial Examples in Deep Neural Networks (2018)

Although deep neural networks (DNNs) have achieved great success in many tasks, they can often be fooled by adversarial examples that are generated by adding small but purposeful distortions to natural examples. Previous studies to defend against adversarial examples mostly focused on refining the DNN models, but have either shown limited success or required expensive computation. We propose a new strategy, feature squeezing, that can be used to harden DNN models by detecting adversarial examples. Feature squeezing reduces the search space available to an adversary by coalescing samples that correspond to many different feature vectors in the original space into a single sample. By comparing a DNN model's prediction on the original input with that on squeezed inputs, feature squeezing detects adversarial examples with high accuracy and few false positives.
Toxicity of Aromatic Ketone to Yeast Cell and Improvement of the Asymmetric Reduction of Aromatic Ketone Catalyzed by Yeast Cell with the Introduction of Resin Adsorption (2008)

Asymmetric reduction of the prochiral aromatic ketone catalyzed by yeast cells is one of the most promising routes to produce its corresponding enantiopure aromatic alcohol, but the space-time yield does not meet people’s expectations. Therefore, the toxicity of aromatic ketone and aromatic alcohol to the yeast cell is investigated in this work. It has been found that the aromatic compounds are poisonous to the yeast cell. The activity of yeast cell decreases steeply when the concentration of acetophenone (ACP) is higher than 30.0 mmol/L. Asymmetric reduction of acetophenone to chiral S-α-phenylethyl alcohol (PEA) catalyzed by the yeast cell was chosen as the model reaction to study in detail the promotion effect of the introduction of the resin adsorption on the asymmetric reduction reaction. The resin acts as the substrate reservoir and product extraction agent in situ. It has been shown that this reaction could be remarkably improved with this technique when the appropriate kind of resin is applied. The enantioselectivity and yield are acceptable even though the initial ACP concentration reaches 72.2 mmol/L.
Novel Dual Inhibitory Function Aptamer–siRNA Delivery System for HIV-1 Therapy (2008)

The successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. In this study, we demonstrate cell type-specific delivery of anti-human immunodeficiency virus (anti-HIV) siRNAs through fusion to an anti-gp120 aptamer. The envelope glycoprotein is expressed on the surface of HIV-1-infected cells, allowing binding and internalization of the aptamer-siRNA chimeric molecules. We demonstrate that the anti-gp120 aptamer-siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and that the appended siRNA is processed by Dicer; this releases an anti-tat/rev siRNA which, in turn, inhibits HIV replication. We show for the first time a dual functioning aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities. We also show that gp120 expressed on the surface of HIV-infected cells can be used for aptamer-mediated delivery of anti-HIV siRNAs.
A control strategy for adaptive bipedal locomotion (1996)

Rhythmic movements of a five-link sagittal biped with muscle-like actuators are considered. In walking contact is periodically made with the environment as the support phases change. The inputs to every actuator are modeled after the inputs to muscles in mammals. The system possesses intrinsic position and velocity feedback due to the actuator dynamics. A control strategy is articulated that is novel in that (a) it is physiologically viable, (b) it simplifies the dynamics, and (c) it adapts to speed of walking, going up and down stairs, going up or dozen inclines, maneuvering above obstacles or holes, and the tempo and stride length of walking. Simulations of the walk of a five-link sagittal biped are presented.
Influencing the influenza virus: genetic analysis and engineering of the negative-sense RNA genome. (1993)

The genome of influenza virus has become amenable to genetic analysis as a result of newly developed methods for reconstitution of the ribonucleoprotein (RNP) complex. This allows a dissection of the regulatory signals and promoters required for transcription and replication of the viral genome. The ability to rescue chimeric viruses in vivo after transfection opens up a way to engineer viruses suitable for human immunization and carrying desirable antigenic determinants.
The Medicinal Use of Cannabis and Cannabinoids—An International Cross-Sectional Survey on Administration Forms (2013)

Cannabinoids, including tetrahydrocannabinol and cannabidiol, are the most important active constituents of the cannabis plant. Over recent years, cannabinoid-based medicines (CBMs) have become increasingly available to patients in many countries, both as pharmaceutical products and as herbal cannabis (marijuana). While there seems to be a demand for multiple cannabinoid-based therapeutic products, specifically for symptomatic amelioration in chronic diseases, therapeutic effects of different CBMs have only been directly compared in a few clinical studies. The survey presented here was performed by the International Association for Cannabinoid Medicines (IACM), and is meant to contribute to the understanding of cannabinoid-based medicine by asking patients who used cannabis or cannabinoids detailed questions about their experiences with different methods of intake. The survey was completed by 953 participants from 31 countries, making this the largest international survey on a wide variety of users of cannabinoid-based medicine performed so far. In general, herbal non-pharmaceutical CBMs received higher appreciation scores by participants than pharmaceutical products containing cannabinoids. However, the number of patients who reported experience with pharmaceutical products was low, limiting conclusions on preferences. Nevertheless, the reported data may be useful for further development of safe and effective medications based on cannabis and single cannabinoids.
A Rare BSEP Mutation Associated with a Mild Form of Progressive Familial Intrahepatic Cholestasis Type 2 (2017)

Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2) is a rare cholestatic disorder diagnosed in infancy or childhood that can lead to severe hepatic fibrosis and liver failure. Mutations in the ABCB11 gene result in a deficiency of the bile salt export protein (BSEP) and accumulation of bile inside the hepatocytes. Hepatocellular carcinoma is another condition associated with severe forms of deletion mutations in the ABCB11 gene. Treatment options including ursodeoxycholic acid biliary diversion have mixed outcomes and some patients require liver transplantation. Here, we describe two siblings with an extremely mild form of PFIC2 inherited from heterozygous parents. The elder sibling had acute liver failure at the age of six months and both siblings had pruritus, cholestasis, coagulopathy and fat-soluble-vitamin deficiencies in infancy but have been asymptomatic past infancy. Genetic testing of the siblings revealed that each were compound heterozygotes for two missense mutations of the ABCB11 gene: p.C68Y and p.R832H. Medical treatment typical for PFIC2 has not been necessary for either patient. This is the first report of these variants following a mild course in two affected patients.
Cyanohydrin synthesis: studies with carbon-13-labeled cyanide (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCyanohydrin synthesis: studies with carbon-13-labeled cyanideAnthony S. Serianni, Hernan A. Nunez, and Robert BarkerCite this: J. Org. Chem. 1980, 45, 16, 3329–3341Publication Date (Print):August 1, 1980Publication History Published online1 May 2002Published inissue 1 August 1980https://pubs.acs.org/doi/10.1021/jo01304a038https://doi.org/10.1021/jo01304a038research-articleACS PublicationsRequest reuse permissionsArticle Views646Altmetric-Citations49LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Expression of angiostatic factors in colorectal cancer. (1999)

Angiogenesis plays an important role in growth and proliferation of cancer. Various angiogenic and angiostatic factors regulate angiogenesis. We examined expression of genes encoding various angiostatic factors: thrombospondin 1 (TSP1), thrombospondin 2 (TSP2), brain-specific angiogenesis inhibitor 1 (BAI1) and angiopoietin 2 (AGP2) in 62 colorectal cancers and 40 samples of extraneoplastic colon mucosa. The expression of the angiostatic factors TSP2 and AGP2 were significantly increased in the cancerous mucosa as compared to these in extraneoplastic mucosa (o2 test; p<0. 0001, and Fisher's exact test; p<0.0001), while the increase in TSP1 expression was not significant. BAI1 expression was slightly decreased in the cancer tissue. These results suggested that specific types of angiostatic factors might have protective roles against cancer cell proliferation via dormancy due to hyponutrition caused by decreased vascularity.
Jasmonates induce nonapoptotic death in high‐resistance mutant p53‐expressing B‐lymphoma cells (2005)

Mutations in p53, a tumor suppressor gene, occur in more than half of human cancers. Therefore, we tested the hypothesis that jasmonates (novel anticancer agents) can induce death in mutated p53-expressing cells. Two clones of B-lymphoma cells were studied, one expressing wild-type (wt) p53 and the other expressing mutated p53. Jasmonic acid and methyl jasmonate (0.25-3 mM) were each equally cytotoxic to both clones, whereas mutant p53-expressing cells were resistant to treatment with the radiomimetic agent neocarzinostatin and the chemotherapeutic agent bleomycin. Neocarzinostatin and bleomycin induced an elevation in the p53 levels in wt p53-expressing cells, whereas methyl jasmonate did not. Methyl jasmonate induced mostly apoptotic death in the wt p53-expressing cells, while no signs of early apoptosis were detected in mutant p53-expressing cells. In contrast, neocarzinostatin and bleomycin induced death only in wt p53-expressing cells, in an apoptotic mode. Methyl jasmonate induced a rapid depletion of ATP in both clones. In both clones, oligomycin (a mitochondrial ATP synthase inhibitor) did not increase ATP depletion induced by methyl jasmonate, whereas inhibition of glycolysis with 2-deoxyglucose did. High glucose levels protected both clones from methyl jasmonate-induced ATP depletion (and reduced methyl jasmonate-induced cytotoxicity), whereas high levels of pyruvate did not. These results suggest that methyl jasmonate induces ATP depletion mostly by compromising oxidative phosphorylation in the mitochondria. In conclusion, jasmonates can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing a nonapoptotic cell death.
Reference points for comparisons of two‐dimensional maps of proteins from different human cell types defined in a pH scale where isoelectric points correlate with polypeptide compositions (1994)

A highly reproducible, commercial and nonlinear, wide-range immobilized pH gradient (IPG) was used to generate two-dimensional (2-D) gel maps of [35S]methionine-labeled proteins from noncultured, unfractionated normal human epidermal keratinocytes. Forty one proteins, common to most human cell types and recorded in the human keratinocyte 2-D gel protein database were identified in the 2-D gel maps and their isoelectric points (pI) were determined using narrow-range IPGs. The latter established a pH scale that allowed comparisons between 2-D gel maps generated either with other IPGs in the first dimension or with different human protein samples. Of the 41 proteins identified, a subset of 18 was defined as suitable to evaluate the correlation between calculated and experimental pI values for polypeptides with known composition. The variance calculated for the discrepancies between calculated and experimental pI values for these proteins was 0.001 pH units. Comparison of the values by the t-test for dependent samples (paired test) gave a p-level of 0.49, indicating that there is no significant difference between the calculated and experimental pI values. The precision of the calculated values depended on the buffer capacity of the proteins, and on average, it improved with increased buffer capacity. As shown here, the widely available information on protein sequences cannot, a priori, be assumed to be sufficient for calculating pI values because post-translational modifications, in particular N-terminal blockage, pose a major problem. Of the 36 proteins analyzed in this study, 18-20 were found to be N-terminally blocked and of these only 6 were indicated as such in databases. The probability of N-terminal blockage depended on the nature of the N-terminal group. Twenty six of the proteins had either M, S or A as N-terminal amino acids and of these 17-19 were blocked. Only 1 in 10 proteins containing other N-terminal groups were blocked.
GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells (2010)

Polycomb proteins are epigenetic regulators that localize to developmental loci in the early embryo where they mediate lineage-specific gene repression. In Drosophila, these repressors are recruited to sequence elements by DNA binding proteins associated with Polycomb repressive complex 2 (PRC2). However, the sequences that recruit PRC2 in mammalian cells have remained obscure. To address this, we integrated a series of engineered bacterial artificial chromosomes into embryonic stem (ES) cells and examined their chromatin. We found that a 44 kb region corresponding to the Zfpm2 locus initiates de novo recruitment of PRC2. We then pinpointed a CpG island within this locus as both necessary and sufficient for PRC2 recruitment. Based on this causal demonstration and prior genomic analyses, we hypothesized that large GC-rich elements depleted of activating transcription factor motifs mediate PRC2 recruitment in mammals. We validated this model in two ways. First, we showed that a constitutively active CpG island is able to recruit PRC2 after excision of a cluster of activating motifs. Second, we showed that two 1 kb sequence intervals from the Escherichia coli genome with GC-contents comparable to a mammalian CpG island are both capable of recruiting PRC2 when integrated into the ES cell genome. Our findings demonstrate a causal role for GC-rich sequences in PRC2 recruitment and implicate a specific subset of CpG islands depleted of activating motifs as instrumental for the initial localization of this key regulator in mammalian genomes.
Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein (1997)

The data provide new insights into the mechanisms underlying human SMC proliferation. Activation of MMP-2 and increased MMP-9 expression are shown to be important components of the response to injury in this model. Furthermore, MMP-9 expression is closely associated with medial and neointimal SMC proliferation.
Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas (2008)

NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically activated upon recognition of all evaluated HER-2 positive tumor cells, including autologous targets, as indicated by high levels of cytokine secretion as well as degranulation. The magnitude of this specific response correlated with the level of HER-2 expression on the tumor cells. Finally, these receptor transduced NK cells, but not their mock transduced counterpart, efficiently eradicated tumor cells in RAG2 knockout mice as visualized by in vivo imaging. Taken together, these results indicate that the expression of this activating receptor overrides inhibitory signals in primary human NK cells and directs them specifically toward HER-2 expressing tumor cells both in vitro and in vivo.
Brain‐derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation (2004)

Brain-derived neurotrophic factor (BDNF) is a candidate molecule for mediating functional neuronal changes in allergic bronchial asthma. Recently, enhanced production of BDNF during allergic airway inflammation caused by infiltrating T-cells and macrophages as well as by resident airway epithelial cells has been described. It was the aim of this study to investigate the effect of enhanced BDNF levels on lung function and airway inflammation in a mouse model of allergic inflammation. Ovalbumin-sensitised BALB/c mice were challenged in two consecutive allergen challenges. Prior to the challenge, the mice were treated with either anti-BDNF antibodies or isotype-matched control antibodies. Airway responsiveness to methacholine, capsaicin and electric field stimulation, as well as airway inflammation and chronic airway obstruction 1 week after the last allergen challenge were assessed. Anti-BDNF blocked enhanced reactivity in response to capsaicin, but not airway smooth muscle hyper-reactivity in vivo. Furthermore, persistent airway obstruction, as observed 1 week after the last allergen challenge, was to a large extent prevented by anti-BDNF treatment. In vitro, BDNF and anti-BDNF treatment had a profound effect on local neuronal hyper-reactivity, as shown by electric field stimulation experiments. In contrast, neither BDNF nor anti-BDNF treatment affected airway inflammation. Our data indicate that development of allergen-induced neuronal hyper-reactivity in mice is partially mediated by BDNF. British Journal of Pharmacology (2004) 141, 431-440. doi:10.1038/sj.bjp.0705638
Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey (2017)

The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested.<sup>24</sup> hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ-inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.