gebhart/patrepeval huggingface dataset:
Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons (2014)

Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.
Colloid Formation by Drugs in Simulated Intestinal Fluid (2010)

Many organic molecules form colloidal aggregates in aqueous solution at micromolar concentrations. These aggregates promiscuously inhibit soluble proteins and are a major source of false positives in high-throughput screening. Several drugs also form colloidal aggregates, and there has been speculation that this may affect the absorption and distribution of at least one drug in vivo. Here we investigate the ability of drugs to form aggregates in simulated intestinal fluid. Thirty-three Biopharmaceutics Classification System (BCS) class II and class IV drugs, spanning multiple pharmacological activities, were tested for promiscuous aggregation in biochemical buffers. The 22 that behaved as aggregators were then tested for colloid formation in simulated intestinal fluid, a buffer mimicking conditions in the small intestine. Six formed colloids at concentrations equal to or lower than the concentrations reached in the gut, suggesting that aggregation may have an effect on the absorption and distribution of these drugs, and potentially others, in vivo.
Duplicated Binding Sites for (1→3)-β-d-Glucan in the Horseshoe Crab Coagulation Factor G (2002)

The horseshoe crab factor G, a heterodimeric serine protease zymogen, is activated by (1-->3)-beta-D-glucan on fungal cell walls. The activation initiates the hemolymph-clotting cascade, a critical reaction for the defense against microorganisms. In the present study, we identified the domain responsible for the glucan recognition by factor G and characterized its interaction with (1-->3)-beta-d-glucan and its derivatives. Among three domains in subunit alpha of factor G, identified as the glucan-binding domain, was the COOH-terminal xylanase Z-like domain composed of two tandem-repeating units, each of which exhibits sequence similarities to the cellulose-binding domains of bacterial xylanases. Each of the single units bound to the glucan with lower affinities, and the association constant increased two orders with the tandem-repeating structure (K(a) = 8.0 x 10(8) m(-1)). In addition to longer glucans, (1-->3)-beta-D-glucan oligosaccharides incapable of activating factor G bound also to factor G and competitively inhibited the zymogen activation. The minimum structure required for the binding was a (1-->3)-beta-d-glucan disaccharide, indicating that conformation-dependent structures are not essential for the recognition. Therefore, increasing avidity by multivalent binding sites with low affinities to simple structures on biologically active polymers may be one of the principles that allows stable and specific recognition of pathogens by pattern recognition receptors in innate immunity.
Insulin-like growth factor-binding protein from human plasma. Purification and characterization. (1986)

Insulin-like growth factor (IGF)-binding protein (BP) has been purified from Cohn fraction IV of human plasma by acidification, ion exchange to remove endogenous ligands, and affinity chromatography on agarose-IGF-II. The pure protein appeared as a single peak by high performance reverse-phase and gel permeation chromatography (molecular mass, 45-50 kDa), but on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gave a major band at 53 kDa and a minor band at 47 kDa, unreduced, or 43 and 40 kDa, respectively, reduced. The two bands stained for both protein and carbohydrate. After storage at 2 degrees C for 5 months at pH 3, two additional bands, at 26 and 22 kDa on unreduced gels, were also present. Autoradiography after affinity labeling with IGF-I or IGF-II tracer revealed a single labeled band of 61 kDa. BP, quantitated using a specific radioimmunoassay, was retained by agarose-immobilized IGF-I, IGF-II, concanavalin A, and wheat germ lectin, but not Helix pomatia lectin. Competitive binding curves using pure BP and human IGF-I and IGF-II as both labeled and unlabeled ligands indicated association constants of 2-3 X 10(10) liters/mol for both peptides, with a slightly higher affinity for IGF-II than IGF-I, and 0.9 binding sites for either peptide per 53-kDa protein. The exact relationship of this acid-stable IGF BP to the 150-kDa complex from which it is derived remains to be determined.
Nonpeptide ligands for human gamma delta T cells. (1994)

gamma delta T cells respond to a variety of microbial pathogens and transformed cells. Their limited receptor repertoire and activation by mycobacterial antigens resistant to proteases suggest that they may recognize nonpeptide antigens. We have tested a variety of nonpeptide molecules for stimulation of human gamma delta T cells. Synthetic alkyl phosphates, particularly monoethyl phosphate (MEP), selectively activated gamma delta T cells and stimulated their proliferation in vitro. All gamma delta T cells stimulated by MEP expressed V gamma 2/V delta 2 receptors. The purified natural ligand of mycobacteria is chemically similar to, though distinct from, MEP and contains a phosphate residue that is critical for biological activity. Recognition and expansion of a specific T-cell receptor-bearing population to non-peptide ligands is unprecedented among T cells. We suggest that MEP mimics small natural ligands capable of expanding one subset of gamma delta T cells and that this recognition of nonpeptide antigens may play an important role in human immunity to pathogens.
A compact manufacturable 76-77-GHz radar module for commercial ACC applications (2001)

The design and measured results of a single-substrate transceiver module suitable for 76-77-GHz pulsed-Doppler radar applications are presented. Emphasis on ease of manufacture and cost reduction of commercial millimeter-wave systems is employed throughout as a design parameter. The importance of using predictive modeling techniques in understanding the robustness of the circuit design is stressed. Manufacturing techniques that conform to standard high-volume assembly constraints have been used. The packaged transceiver module, including three waveguide ports and intermediate-frequency output, measures 20 mm/spl times/22 mm/spl times/8 mm. The circuit is implemented using discrete GaAs/AlGaAs pseudomorphic high electron mobility transistors (pHEMTs), GaAs Schottky diodes, and varactor diodes, as well as GaAs p-i-n and pHEMT monolithic microwave integrated circuits mounted on a low-cost 127-/spl mu/m-thick glass substrate. A novel microstrip-to-waveguide transition is described to transform the planar microstrip signal into the waveguide launch. The module is integrated with a quasi-optical antenna. The measured performance of both the component parts and the complete radar transceiver module is described.
Deep brain stimulation in movement disorders: stereotactic coregistration of two-dimensional electrical field modeling and magnetic resonance imaging (2005)

The electrical field is a crucial parameter because it is assumed to be responsible for triggering action potentials. Electrical field visualization allows the calculation of the stimulated volume for a given isoline. Its application to an entire series of patients may help determine a threshold for obtaining a therapeutic effect, which is currently unknown, and consequently may aid in optimizing parameter settings in individual patients.
A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells (2007)

Nanog is a critical homeodomain factor responsible for maintaining embryonic stem (ES) cell self-renewal and pluripotency. Of interest, Nanog expression is not homogeneous in the conventional culture of murine ES cells. A Nanog-high population expresses markers for pluripotent ES cells, whereas a Nanog-low population expresses markers for primitive endoderm, such as Gata6. Since the inner cell mass of early blastocysts has recently been reported to be heterogeneous in terms of Nanog and Gata6 expression, ES cells appear to closely resemble the developing stage from which they originate. We further demonstrate that Nanog can directly repress Gata6 expression through its binding to the proximal promoter region of the Gata6 gene and that overexpression of Nanog reduces heterogeneity during ES cell maintenance. Interestingly, Nanog heterogeneity does not correlate with the heterogeneous expression of stage-specific embryonic antigen-1, suggesting that multiple but overlapping levels of heterogeneity may exist in ES cells. These findings provide insight into the factors that control ES cell self-renewal and the earliest lineage commitment to primitive endoderm while also suggesting methods to promote homogeneity during ES cell maintenance. Disclosure of potential conflicts of interest is found at the end of this article.
Concentration and molecular weight dependency of rabbit corneal epithelial wound healing on hyaluronan (1992)

Hyaluronan (hyaluronic acid) is a high molecular weight viscoelastic polymer which has been postulated to enhance wound healing. We investigated the dose and molecular weight (9 x 10(4)-280 x 10(4) dependent effects of hyaluronan on the rate of migration of rabbit corneal epithelium in organ culture and on wound closure in vivo after debridement with n-heptanol. When corneal blocks were cultured with hyaluronan for 20 hours, distances of epithelial migration significantly increased over exposed stroma in proportion to hyaluronan concentration. However, there was no difference in the stimulatory action of hyaluronan on epithelial migration when corneal blocks were cultured at 1 mg/ml of hyaluronan irrespective of changes in the molecular weight range between 9 x 10(4) and 280 x 10(4). Glycosaminoglycans other than hyaluronan (chondroitin, chondroitin sulfate, keratan sulfate and heparan sulfate) failed to increase the epithelial migration. When hyaluronan eye drops were instilled after corneal epithelial removal with n-heptanol, hyaluronan stimulated wound closure in a dose-dependent manner, but its stimulatory efficacy was not dependent on molecular weight.
Joint optimization of scale factors and huffman code books for MPEG-4 AAC (2005)

The MPEG-4 AAC audio encoder achieves low bit rates by appropriately choosing the two encoding parameters Huffman code books and scale factors. Existing AAC implementations solve the implied optimization problem using an heuristic two loop search. This paper presents two novel optimization techniques that for the first time find optimal solutions for the AAC optimization problem.
Proposal of a neotype strain (A1-86) for Eubacterium rectale. Request for an Opinion (2008)

Eubacterium rectale is one of the most abundant bacterial species recovered from human faeces. E. rectale (Hauduroy et al. 1937) appears in the 'List of Bacterial Names with Standing in Nomenclature', but it is noted that the originally proposed type strain, VPI 0989(T), has been lost and its possible replacement by another strain (VPI 0990) from the same faecal sample has never been formally proposed. It is therefore proposed that strain A1-86 (=DSM 17629=NCIMB 14373), isolated from human adult faeces, be formally recognized as the neotype strain of Eubacterium rectale.
Specific-primer-directed DNA sequencing using automated fluorescence detection (1989)

Automated fluorescence-based DNA sequence analysis offers the possibility to undertake very large scale sequencing projects. Directed strategies, such as the specific-primer-directed sequencing approach ('gene walking'), should prove useful in such projects. Described herein is a study involving the use of this approach in conjunction with automated fluorescence detection on a commercial instrument (ABI 370A DNA sequencer). This includes procedures for the rapid chemical synthesis and purification of labeled primers, the design of primer sequences that are compatible with the commercial analysis software, and automated DNA sequence analysis using such primers. A set of four fluorophore-labeled primers can be reliably synthesized in a twenty-four hour period, and greater than 300 nucleotides of analyzed new sequence obtained using this set in an additional twenty-four hours. Scale-up of these procedures to take advantage of the full capabilities of the sequencer is, at present, too slow and costly to be suitable for routine sequencing, and therefore the use of specific-primers is best suited to the closure of gaps in extended sequence produced using random cloning and sequencing strategies.
Targeting autophagic pathways for cancer drug discovery (2012)

Autophagy, an evolutionarily conserved lysosomal degradation process, has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.
Rescue of Degradation‐Prone Mutants of the FK506‐Rapamycin Binding (FRB) Protein with Chemical Ligands (2007)

We recently reported that certain mutations in the FK506-rapamycin binding (FRB) domain disrupt its stability in vitro and in vivo (Stankunas et al. Mol. Cell, 2003, 12, 1615). To determine the precise residues that cause instability, we calculated the folding free energy (Delta G) of a collection of FRB mutants by measuring their intrinsic tryptophan fluorescence during reversible chaotropic denaturation. Our results implicate the T2098L point mutation as a key determinant of instability. Further, we found that some of the mutants in this collection were destabilized by up to 6 kcal mol(-1) relative to the wild type. To investigate how these mutants behave in cells, we expressed firefly luciferase fused to FRB mutants in African green monkey kidney (COS) cell lines and mouse embryonic fibroblasts (MEFs). When unstable FRB mutants were used, we found that the protein levels and the luminescence intensities were low. However, addition of a chemical ligand for FRB, rapamycin, restored luciferase activity. Interestingly, we found a roughly linear relationship between the Delta G of the FRB mutants calculated in vitro and the relative chemical rescue in cells. Because rapamycin is capable of simultaneously binding both FRB and the chaperone, FK506-binding protein (FKBP), we next examined whether FKBP might contribute to the protection of FRB mutants. Using both in vitro experiments and a cell-based model, we found that FKBP stabilizes the mutants. These findings are consistent with recent models that suggest damage to intrinsic Delta G can be corrected by pharmacological chaperones. Further, these results provide a collection of conditionally stable fusion partners for use in controlling protein stability.
Cloning and expression of a protective antigen from the cattle tick Boophilus microplus. (1989)

Glycoproteins located on the luminal surface of the plasma membrane of tick gut epithelial cells, when used to vaccinate cattle, are capable of stimulating an immune response that protects cattle against subsequent tick infestation. One such tick gut glycoprotein, designated Bm86, has been purified to homogeneity and the amino acid sequences of peptide fragments generated by endoproteinase Lys-C digestion have been determined. We report here the isolation and characterization of a cDNA that encodes Bm86. The nucleotide sequence of the cDNA contains a 1982-base-pair open reading frame and predicts that Bm86 contains 650 amino acids including a 19-amino acid signal sequence and a 23-amino acid hydrophobic region adjacent to the carboxyl terminus. The main feature of the deduced protein sequence is the repeated pattern of 6 cysteine residues, suggesting the presence of several epidermal growth factor-like domains. A fusion protein consisting of 599 amino acids of Bm86 and 651 amino acids of beta-galactosidase was expressed in Escherichia coli as inclusion bodies. Ticks engorging on cattle vaccinated with these inclusion bodies were significantly damaged as a result of the immune response against the cloned antigen.
ChemInform Abstract: Preparation of Substituted 2‐Aminooxazole‐4‐carbonitriles. (1989)

Abstract During a synthetic program to convert thioureas of type (I) into the carbodiimides (II), a side reaction leading to the aminooxazole carbonitriles (III) is observed.
HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells (1989)

To analyze the nature of the HLA class II-restricted cytotoxic T-lymphocyte (CTL) response to measles virus, murine fibroblasts were transfected with expressible cDNA clones for human HLA-DR antigen and for measles virus matrix or nucleocapsid proteins. DR-positive murine fibroblasts transfected with measles virus matrix or nucleocapsid genes were lysed by class II-restricted measles virus-specific CTL lines. Lysis was as efficient as with infected autologous B-cell lines, even though the measles virus cytoplasmic proteins were undetectable by antibodies in the transfected target cells. These results demonstrate that cytoplasmic viral antigens can be presented to CTL in the context of HLA class II antigens and that measles virus matrix and nucleocapsid proteins contribute to class II-restricted measles virus-specific CTL responses. These results also show that endogenously synthesized measles virus proteins can be efficiently presented by class II antigens. The implications of these findings for measles virus pathogenesis and for antigen processing are discussed.
Platelet activation leads to increased c-src kinase activity and association of c-src with an 85-kDa tyrosine phosphoprotein. (1992)

We have used platelets as a model system to study the function of c-src in signal transduction and cell adhesion. Numerous proteins were found to be phosphorylated on tyrosine in response to thrombin-induced platelet activation and aggregation. Two phases of phosphorylation were observed, with the second phase, but not the first, being inhibited by blocking platelet aggregation with an Arg-Gly-Asp-Ser tetrapeptide. As a first step towards identifying those proteins phosphorylated on tyrosine and to determine the specific role of p60src during platelet activation, we looked for changes in p60src kinase activity and for associations of p60src with other tyrosine phosphoproteins. The data presented here demonstrate an increase in p60src kinase activity within 1 min of thrombin-induced activation. Furthermore, p60src transiently associates with a tyrosine phosphoprotein during platelet activation and aggregation. This tyrosine phosphoprotein, p80/85, is a previously characterized cytoskeletal substrate for v-src in transformed cells. The data presented here suggest a model in which p60src functions in platelets to link upstream events, such as cell-surface adhesive interactions, with changes in platelet shape and cytoskeletal organization.
BotMiner: clustering analysis of network traffic for protocol- and structure-independent botnet detection (2008)

Botnets are now the key platform for many Internet attacks, such as spam, distributed denial-of-service (DDoS), identity theft, and phishing. Most of the current botnet detection approaches work only on specific botnet command and control (C&amp;amp;C) protocols (e.g., IRC) and structures (e.g., centralized), and can become ineffective as botnets change their C&amp;amp;C techniques. In this paper, we present a general detection framework that is independent of botnet C&amp;amp;C protocol and structure, and requires no a priori knowledge of botnets (such as captured bot binaries and hence the botnet signatures, and C&amp;amp;C server names/addresses). We start from the definition and essential properties of botnets. We define a botnet as a coordinated group of malware instances that are controlled via C&amp;amp;C communication channels. The essential properties of a botnet are that the bots communicate with some C&amp;amp;C servers/peers, perform malicious activities, and do so in a similar or correlated way. Accordingly, our detection framework clusters similar communication traffic and similar malicious traffic, and performs cross cluster correlation to identify the hosts that share both similar communication patterns and similar malicious activity patterns. These hosts are thus bots in the monitored network. We have implemented our BotMiner prototype system and evaluated it using many real network traces. The results show that it can detect real-world botnets (IRC-based, HTTP-based, and P2P botnets including Nugache and Storm worm), and has a very low false positive rate. 1