gebhart/patrepeval huggingface dataset:
Lipopolysaccharide-Induced Expression of NAD(P)H:Quinone Oxidoreductase 1 and Heme Oxygenase-1 Protects against Excessive Inflammatory Responses in Human Monocytes (2008)

Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines TNF-alpha and IL-1beta. The transcription factor NF-E2-related factor 2 (Nrf2) regulates innate immune responses in various experimental disease models. Presently, the role of Nrf2-regulated genes in LPS-treated human monocytes is not well defined. Herein we show that Nrf2 mediates a significant regulation of LPS-induced inflammatory responses. Analysis of Nrf2-regulated gene expression in human monocytes showed that LPS induced the expression of the phase II detoxification gene NAD(P)H:quinone oxidoreductase 1 (NQO1). Furthermore, NQO1 mRNA or protein expression in response to LPS was regulated by Nrf2. Silencing Nrf2 expression in human monocytes inhibited LPS-induced NQO1 expression; however, in contrast, it significantly increased TNF and IL-1beta production. Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced TNF and IL-1beta expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1beta expression. These results show for the first time that LPS induces NQO1 and HO-1 expression in human monocytes via Nrf2 to modulate their inflammatory responsiveness, thus providing novel potential therapeutic strategies for the treatment of sepsis.
9.7 a self-calibrated 10mb/s phase modulator with -37.4db evm based on a 10.1-to-12.4ghz, -246.6db-fom, fractional-n subsampling pll (2016)

The two-point injection scheme has proven to be an effective technique for overcoming the problem of PLL bandwidth limitations during wideband polar phase modulation [1]. The quality of the phase-modulated signal, typically expressed in terms of error-vector magnitude (EVM), still remains limited by the PLL phase-noise, gain mismatch between the two injection paths and linearity of the digital-to-modulated phase conversion. We present a phase modulator that makes use of an analog, fractional-N, digital-to-time-converter (DTC)-based subsampling PLL that achieves -37.4dB EVM around a 10.24GHz fractional carrier during 10Mb/s GMSK modulation. The subsampling PLL architecture uses no power-consuming divider and allows wide PLL bandwidth (because of its high phase-error detection gain) for optimal VCO noise suppression. The VCO has a secondary, digitally controlled capacitor bank (modulating DAC) used during two-point modulation. The gain errors and nonlinearities in the digital-to-modulated phase conversion are automatically background-calibrated in both injection points: in the phase-error detection path (where nonlinearity is dominated by the DTC INL) and in the VCO modulating capacitor bank (where nonlinearity is dominated by capacitor mismatch and nonlinear capacitance-to-frequency conversion).
High-frequency transfer of cloned herpes simplex virus type 1 sequences to mammalian cells by protoplast fusion. (1981)

The protoplast fusion technique of Schaffner (W. Schaffner, Proc. Natl. Acad. Sci. U.S.A. 77:2163-2167, 1980) has been adapted to introduce cloned herpes simplex virus genes into cultured mammalian cells. The technique involves digesting bacterial cell walls with lysozyme to produce protoplasts and then fusing the protoplasts to mammalian cells by treatment with polyethylene glycol. For monitoring transfer, protoplasts were labeled with the fluorescent dye fluorescein isothiocyanate before fusion. After fusion, greater than 50% of the mammalian cells were fluorescent, demonstrating that bacterial material was transferred with high frequency. Transfer of plasmid pBR325 occurred at frequencies of 1 to 2%, as measured by in situ hybridization. Fusion transfer of a chimeric plasmid consisting of the herpes simplex virus type 1 (strain KOS) EcoRI fragment F in pBR325 resulted in expression of some viral genomic sequences in about 5% of the mammalian cells, as detected by indirect immunofluorescence. One Ltk- cell in 300 to 500 was transformed to the TK+ phenotype after fusion with protoplasts carrying the chimeric plasmid pX1, which consists of pBR322 and the BamHI fragment coding for the herpes simplex virus type 1 thymidine kinase gene.
Proteomic and Functional Investigation of the Colon Cancer Relapse-Associated Genes NOX4 and ITGA3 (2014)

Colon cancer is a major cause of cancer-related deaths worldwide. Adjuvant chemotherapy significantly reduces mortality in stage III colon cancer; however, it is only marginally effective in stage II patients. There is also increasing evidence that right-side colon cancer is different from left-side colon cancer. We have observed that the genes altered in expression between the poor and good prognosis tumors vary significantly depending on whether the malignancy originates on the right or left side of the colon. We have identified NADPH oxidase 4 (NOX4) to be highly predictive of relapse in stage II left-side colon cancer, whereas integrin alpha 3 beta 1 (ITGA3) is predictive of relapse in stage II right-side colon cancer. To investigate the underlying molecular mechanisms, we are analyzing the effect of ITGA3 and NOX4 silencing via RNA interference and pharmacological inhibition on global protein expression patterns via iTRAQ labeling and mass spectrometry in colon cancer cells. On the basis of bioinformatic analysis, the functions of these genes were assessed through phenotypic assays, revealing roles in cell migration and reactive oxygen species generation. These biomarkers for relapse risk are of clinical interest and lead to insight into how a tumor progresses to metastasis.
Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt (2009)

Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin (BV) to bilirubin (BR) in all cells. Others and we have shown that biliverdin is a potent anti-inflammatory molecule, however, the mechanism by which BV exerts its protective effects is unclear. We describe and elucidate a novel finding demonstrating that BVR is expressed on the external plasma membrane of macrophages (and other cells) where it quickly converts BV to BR. The enzymatic conversion of BV to BR on the surface by BVR initiates a signaling cascade through tyrosine phosphorylation of BVR on the cytoplasmic tail. Phosphorylated BVR in turn binds to the p85alpha subunit of phosphatidylinositol 3-kinase and activates downstream signaling to Akt. Using bacterial endotoxin (lipopolysaccharide) to initiate an inflammatory response in macrophages, we find a rapid increase in BVR surface expression. One of the mechanisms by which BV mediates its protective effects in response to lipopolysaccharide is through enhanced production of interleukin-10 (IL-10) the prototypical anti-inflammatory cytokine. IL-10 regulation is dependent in part on the activation of Akt. The effects of BV on IL-10 expression are lost with blockade of Akt. Inhibition of surface BVR with RNA interference attenuates BV-induced Akt signaling and IL-10 expression and in vivo negates the cytoprotective effects of BV in models of shock and acute hepatitis. Collectively, our findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR)(surf) modulates the inflammatory response.
Analysis of the S3 and S3′ subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo (1998)

The S3 and S3' subsite binding specificities of HIV and feline immunodeficiency virus proteases (FIV) proteases (PRs) have been explored by using C2-symmetric competitive inhibitors. The inhibitors evaluated contained (1S, 2R, 3R, 4S)-1,4-diamino-1, 4-dibenzyl-2,3-diol as P1 and P1' units, Val as P2 and P2' residues, and a variety of amino acids at the P3 and P3' positions. All inhibitors showed very high potency against HIV PR in vitro, and their Ki values ranged between 1.1 and 2.6 nM. In contrast to the low restriction of P3 and P3' residues observed in HIV PR, FIV PR exhibited strong preference for small hydrophobic groups at the S3 and S3' subsites. Within this series, the most effective inhibitor against FIV PR contained Ala at P3 and P3'. Its Ki of 41 nM was 415- and 170-fold lower than those of the inhibitors without the P3 and P3' moieties or with the Phe at these positions, respectively. In addition, these compounds were tested against mutant FIV PRs, which contain amino acid substitutions corresponding to those in native HIV PR at homologous sites, and their efficacy of inhibition progressively increased up to 5-fold. The most potent FIV PR inhibitor was selected for examination of its effectiveness in tissue culture, and it was able to block nearly 100% of virus production in an acute infection at 1 microg/ml (1.1 microM) against HIV, FIV, and simian immunodeficiency virus. Furthermore, it was not toxic to cells, and even after 2 months of culture there was no sign of resistance development by virus. The findings suggest that inhibitors with small P3 residue may be efficacious against a broad range of HIV variants as well as interspecies PRs.
Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site (2001)

We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors.
Comprehensive Mapping of Poxvirus vCCI Chemokine-binding Protein (2002)

In compiling a comprehensive map of the ligand binding capacity of elements within the chemokine system, we have determined the spectrum of chemokines capable of interacting with the poxvirus-encoded viral CC chemokine inhibitor, vCCI. More than 80 chemokines were tested in parallel for their ability to displace radiolabeled signature chemokines from vCCI. Of these chemokines, 26 showed potential high affinity interactions. These interactions revealed an expanded spectrum of binding capacity for vCCI to now include molecules such as human myeloid progenitor inhibitory factor-1 as ligands. In addition, high affinity viral protein-protein interactions were revealed. For example, binding between poxvirus vCCI and the herpesvirus vMIP-II from HHV8 occurs with IC(50) approximately 10-50 nm. Unusual dissociation kinetics were observed between certain chemokines and vCCI. Notably, many ligands displayed a precipitous displacement profile, suggesting marked positive cooperativity of binding. Finally, heterologous competition provided evidence for overlapping but distinct binding sites for the many chemokines that bind to vCCI. The determination of the binding fingerprint and unusual binding interactions of vCCI with a large number of chemokines suggest a finely honed evolutionary strategy of chemokine sequestration during viral infection.
Unlocking the opportunity of tight glycaemic control (2005)

Numerous attempts have been made to develop novel routes of insulin delivery that are both effective and tolerable. Of all the potential non-invasive delivery options, pulmonary delivery is the most clinically viable. Early studies demonstrate that the inhaled insulin is rapidly absorbed and is closer to biological insulin than standard subcutaneous insulin (SC). To date, inhaled insulin (Exubera) has been clinically assessed in more than 3500 patients with type 1 or type 2 diabetes, some treated for more than 7 years. Several phase 3 studies of 24-week duration have demonstrated comparable glycosylated haemoglobin (HbA1c) control in patients with type 1 diabetes treated with Exubera vs. SC insulin. Similar results have also been recorded in patients with type 2 diabetes. Furthermore, Exubera has shown clinical superiority to oral agent regimens in patients with type 2 diabetes who failed to achieve their target HbA1c using lifestyle modification and oral agents. Exubera was well tolerated and treatment satisfaction was high, with Exubera being the preferred insulin therapy in all studies. The results of these trials, and others, suggest that Exubera may be a valuable tool to help a wide variety of patients with type 1 or type 2 diabetes reach their recommended goals for glycaemic control, irrespective of their current therapy.
Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children (1992)

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.
Total Synthesis of (+)-Yatakemycin (2006)

A convergent total synthesis of (+)-yatakemycin was accomplished in a 20-step sequence in an overall yield of 13%. The synthesis features the regioselective ring opening of (S)-epichlorohydrin with 2,6-dibromophenyllithium species, the mild copper-mediated aryl amination utilizing the combination of CuI and CsOAc, and the efficient deprotection of benzyl groups of aryl benzyl ether with BCl3 in the presence of pentamethylbenzene.
欧共体“机会均等”的理论与实践 (1993)

一、导论《罗马条约》在论述欧洲共同体之目标时指出,欧共体就是为欧洲人民之间建立一个更加紧密的联盟而奠定基础,同时,通过采取旨在消除分裂欧洲各种障碍的共同行动来确保欧共体各国社会和经济的进步。在这个伟大的目标宣布之时,欧共体就担负起了重要的责任,而这个责任的一个重要方面,就是推行一种“所有欧洲人机会均等”的社会政策。如果机会均等被承认是一项人类的基本
CD45 regulates signal transduction and lymphocyte activation by specific association with receptor molecules on T or B cells. (1988)

Evidence is presented that the leukocyte common antigen CD45 can regulate both signal transduction by lymphocyte receptor molecules and T- and B-cell proliferation in a manner dependent on specific interactions between these receptors on the cell surface. Formation of homoaggregates of CD3, CD2, or CD28 on the surface of T cells induced by crosslinking with monoclonal antibodies (mAbs) results in an increase in cytoplasmic free calcium concentration ([Ca2+]i). This increase in [Ca2+]i was abolished when these receptors were crosslinked to CD45 on the cell surface. In contrast, the increase in [Ca2+]i induced by formation of homoaggregates of CD4 was strongly amplified when CD4 was coupled to CD45. T-cell proliferation initiated by immobilized anti-CD3 was inhibited by anti-CD45 or anti-CD45R when immobilized on the same surface, but not when in solution. Similarly, proliferation after stimulation of the CD2 and CD28 receptors was inhibited when a CD45 mAb was crosslinked to either CD2 or CD28 mAbs, but not when a CD45-specific mAb was bound to the cell surface separately. In B cells, the increase in [Ca2+]i and resulting proliferation induced by crosslinking either the CD19 or Bgp95 receptors was inhibited by coupling these molecules to CD45. Thus, CD45 appears to modify other cellular receptors functionally when brought into close physical association with them. The homology of the CD45 conserved cytoplasmic domains with a major human placental protein tyrosine phosphatase suggests that the effects of CD45 described here result from alterations in the phosphorylation state of tyrosyl residues in membrane-associated proteins.
Construction and properties of replication-competent murine retroviral vectors encoding methotrexate resistance. (1989)

A series of replication-competent Moloney murine leukemia virus vectors was constructed in which each vector contained a mutant dihydrofolate reductase (DHFR) cDNA insert in the U3 region of the viral long terminal repeat. Two of the resulting viruses, MLV (murine leukemia virus) DHFR*-5 and MLV DHFR*-7, were able to stably transfer methotrexate resistance to infected fibroblast cells upon multiple rounds of virus replication and in the absence of drug selection. Cell lines producing recombinant virus with high titers were established, which indicated that the insert did not grossly interfere with viral replication functions. These vectors should be useful for introducing and expressing foreign genes in vivo in tissues and whole animals in which virus spread is needed for efficient infection.
Surface-enhanced Laser Desorption/Ionisation Time-of-flight Mass Spectrometry to Detect Breast Cancer Markers in Tears and Serum. (2009)

Protein chip technology facilitates the discovery of new and better biomarkers in breast cancer. It is a promising approach to analyse a large number of patients with high sensitivity and specificity. Analysing tear fluid could show some advantages.
1-[2-Methoxy-5-(3-phenylpropyl)]-2-aminopropane Unexpectedly Shows 5-HT2A Serotonin Receptor Affinity and Antagonist Character (2001)

Certain phenylethylamines, such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a), are high-affinity 5-HT2 agonists. Previous structure−affinity studies have concluded that both the 2,5-dimethoxy substitution pattern and the nature of substituents at the 4-position are important determinants of high affinity. We recently demonstrated that replacement of the bromo group of DOB with a 3-(phenyl)propyl substituent results in retention of affinity and that, counter to established structure−affinity relationships, the 2,5-dimethoxy substitution pattern is no longer a requirement for the binding. The present investigation extends these findings by examining a series of analogues, 3, lacking a 5-methoxy group. It was additionally found that shifting the phenylalkyl substituent from the 4- to the 5-position (e.g., 4i) also results in retention of affinity. For example, 1-(2-methoxy-5-(3-phenylpropyl)-2-aminopropane (6; the α-methyl derivative of 4i) binds at 5-HT2A receptors with high affinity (Ki = 13 nM) and possesses 5-HT2A antagonist character. Thus, not only is the 2,5-dimethoxy substitution pattern not a requirement for the binding of certain phenylethylamines at 5-HT2A receptors, the presence of a 4-position substituent (previously thought to serve as a modulator of affinity of DOB-like agents) is also not required. Striking differences in the 5-HT2A binding requirements of the present compounds as compared to DOB-like agents suggest multiple substituent-dependent modes of binding.
daf-2 , an Insulin Receptor-Like Gene That Regulates Longevity and Diapause in Caenorhabditis elegans (1997)

A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
Serum constituents can affect 2′‐& 3′‐O‐(4‐benzoylbenzoyl)‐ATP potency at P2X7 receptors (2001)

1. 2'-& 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) is the prototypic agonist for P2X(7) receptors. In this study we demonstrate that bovine serum albumin (BSA) can affect the potency of BzATP at P2X receptors. 2. BzATP potency (pEC(50)) to stimulate ethidium accumulation in cells expressing recombinant P2X7 receptors varied between 6.5 and 4, depending upon the species orthologue studied and ionic conditions employed. BSA (0.1 - 1 mg ml(-1)) and foetal bovine serum (FBS, 1 - 10% v v(-1)) inhibited responses to BzATP but only when the BzATP pEC(50) exceeded 5. 3. BSA did not block ATP-stimulated ethidium accumulation, suggesting its effects were independent of P2X(7) receptor blockade. 4. BSA did not cause breakdown of nucleotides, although FBS (10% v v(-1)) exhibited appreciable nucleotidase activity and caused significant breakdown of ATP. 5. In the presence of BSA, lipids such as 11-((5-dimethylaminonaphthalene-1-sulphonyl)amino)undecanoic acid (DAUDA) and arachidonic acid (AA) markedly increased BzATP potency. Lipids had no affect on ATP potency in the presence of BSA and had little effect on responses to BzATP in the absence of BSA. 6. These results suggested that the reduction in BzATP potency by BSA was due to BzATP binding to BSA and that lipids prevented this binding. Consistent with this hypothesis, BzATP inhibited binding of the fluorescent lipid, DAUDA, to BSA. 7. In conclusion, BSA and lipids can markedly affect BzATP potency at P2X(7) receptors but this is probably a consequence of BzATP binding to BSA. This finding has important implications when using BzATP in vivo or in the presence of albumin.
Energy-aware video streaming with QoS control for portable computing devices (2004)

We propose an energy-aware video streaming system for portable computing devices, in which the video can be played back for the specified duration within the remaining battery amount. To save power, we introduce techniques (i) to reduce playback quality of a video at an intermediate proxy and (ii) to shorten working time of the network I/F card using periodic bulk transfer of the video data on the wireless LAN. To enable playback for the specified duration, we have developed a power consumption model for portable devices using parameters on playback quality, playback duration, battery amount, and so on. We have also developed an algorithm to assign different playback quality among multiple video segments based on the user's preference.within the battery amount. Our experiments using PDAs and laptop PCs on 802.11b WLAN show that our system achieves less than 6 prediction error in playback duration while adapting playback quality among video segments.