gebhart/patrepeval huggingface dataset:
Microwave generation with low residual phase noise from a femtosecond fiber laser with an intracavity electro-optic modulator (2011)

Low phase-noise microwave generation has previously been demonstrated using self-referenced frequency combs to divide down a low noise optical reference. We demonstrate an approach based on a fs Er-fiber laser that avoids the complexity of self-referenced stabilization of the offset frequency. Instead, the repetition rate of the femtosecond Er-fiber laser is phase locked to two cavity-stabilized cw fiber lasers that span 3.74 THz by use of an intracavity electro-optic modulator with over 2 MHz feedback bandwidth. The fs fiber laser effectively divides the 3.74 THz difference signal to produce microwave signals at harmonics of the repetition rate. Through comparison of two identical dividers, we measure a residual phase noise on a 1.5 GHz carrier of -120 dBc/Hz at 1 Hz offset.
Synthesis of 2,5-disubstituted benzimidazoles, 1,3,4-thiadiazoles and 3,5-diiodosalicylanilides as structural congeners of rafoxanide and closantel. (1990)

The synthesis of a series of 2,5-disubstituted benzimidazoles (8-10, 13), substituted 3,5-diodosalicylanilides (6, 7, 11, 12, 16-29), 2-(4-substituted phenyl)-4-aroylamino-1,3,4-thiadiazoles (33-38) and benzoxazines (14, 30, 31) has been carried out as the structural congeners of rafoxanide and closantel. All the compounds have been tested for their anthelmintic activity against Ancylostoma ceylanicum, Nippostrongylus brasiliensis, Hymenolepis nana and Cysticecus fasciolaris in rodents. Compounds 8, 22 and 23 exhibited 90-100% elimination of the hookworms A. ceylanicum and tapeworms H. nana from hamsters and rats, respectively, at an oral dose 50-250 mg/kg body mass.
PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. (1997)

PD153035 is reported to be a specific and potent inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase and, to a lesser degree, of the closely related HER2/neu receptor. We show that PD153035 inhibits EGF-dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor-overexpressing human cancer cell lines. EGF receptor autophosphorylation in response to exogenous EGF was completely inhibited at PD153035 concentrations of >75 nM in cells overexpressing the EGF receptor. In contrast, PD153035 only reduced heregulin-dependent tyrosine phosphorylation in HER2/neu-overexpressing cell lines at significantly higher concentrations (1400-2800 nM). PD153035 exposure did not affect the expression of either EGF receptors or HER2/neu. PD153035 caused a dose-dependent growth inhibition of EGF receptor-overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested. At doses of up to 2.5 microM, the IC50 for HER2/neu-overexpressing cells was not reached. In colony-forming assays, the PD153035 growth-inhibitory activity in cultures driven by endogenous (autocrine) ligand was correlated with EGF receptor number, with higher activity in cells expressing higher numbers of EGF receptors and only minimal activity in cells expressing normal numbers of EGF receptors but high HER2/neu levels. PD153053 also abolished all growth effects mediated by the addition of exogenous EGF; this condition could be reversed upon removal of the compound. Cotreatment with C225, an anti-EGF receptor-blocking monoclonal antibody, further enhanced the antitumor activity of PD153035, suggesting mechanisms of action for C225 other than competition with ligand binding. This latter finding also suggests that combined anti-EGF receptor strategies may be of enhanced benefit against tumors with high levels of EGF receptor expression.
Glass Vials for Small Volume Parenterals: Influence of Drug and Manufacturing Processes on Glass Delamination (2001)

These results demonstrate the importance of the surface morphology created during the vial forming process. Given the diferences observed, final vial selection should include extensive microscopical and product stress testing studies on multiple vial lots.
Molecular Mechanisms Underlying FOXP3 Induction in Human T Cells (2006)

FOXP3 is playing an essential role for T regulatory cells and is involved in the molecular mechanisms controlling immune tolerance. Although the biological relevance of this transcription factor is well documented, the pathways responsible for its induction are still unclear. The current study reveals structure and function of the human FOXP3 promoter, revealing essential molecular mechanisms of its induction. The FOXP3 promoter was defined by RACE, cloned, and functionally analyzed using reporter-gene constructs in primary human T cells. The analysis revealed the basal, T cell-specific promoter with a TATA and CAAT box 6000 bp upstream the translation start site. The basal promoter contains six NF-AT and AP-1 binding sites, which are positively regulating the trans activation of the FOXP3 promoter after triggering of the TCR. The chromatin region containing the FOXP3 promoter was bound by NF-ATc2 under these conditions. Furthermore, FOXP3 expression was observed following TCR engagement. Promoter activity, mRNA, and protein expression of T cells were suppressed by addition of cyclosporin A. Taken together, this study reveals the structure of the human FOXP3 promoter and provides new insights in mechanisms of addressing T regulatory cell-inducing signals useful for promoting immune tolerance. Furthermore, the study identifies essential, positive regulators of the FOXP3 gene and highlights cyclosporin A as an inhibitor of FOXP3 expression contrasting other immunosuppressants such as steroids or rapamycin.
Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). (2014)

5011 Background: Metastatic UBC is associated with a poor prognosis and limited treatment options. PD-L1 expression is prevalent in this disease and may protect cancer cells from immune-mediated destruction by binding to its receptors PD-1 and B7.1. MPDL3280A is a human anti-PD-L1 mAb with an engineered Fc-domain designed for optimized efficacy and safety. Methods: In a Ph I study, UBC pts received MPDL3280A 15 mg/kg IV q3w for up to 1 y. Objective response rate (ORR; including unconfirmed responses) was assessed by RECIST v1.1. In parallel, tumor and circulating biomarkers were evaluated to study MPDL3280A immune correlates. Results: As of Sep 19, 2013, 31 UBC pts were treated with MPDL3280A. Pts were 84% male, had a median age of 66 y (42-86), 57% were ECOG PS 1 and 68% had visceral metastases. 71% received ≥ 2 prior therapies; 97% received prior platinum-based chemotherapy. Pts had received MPDL3280A for a median duration of 43 d (1-153); the majority remained on treatment as of the data cutoff. The G1-4 treatment-related AEs occurring in ≥ 2 pts were pyrexia, anemia, decreased appetite, fatigue and nausea. Related G3-4 AEs occurred in 3.2% of pts. There were no immune-related AEs. 20 PD-L1+ pts were evaluable for efficacy at time of analysis with a median follow up of 2.8 m (1.4-5). The ORR was 50% (1 CR and 9 PRs) with a median time to response of 43 d (39-82), corresponding to the first radiographic assessment. Responders included pts with visceral metastases at baseline. All responders were still responding at the time of clinical cutoff. Treatment resulted in transient increases in circulating CD8+Ki-67+ T cells and plasma proteins (eg, IL-18) upstream of IFNγ signaling, representing pharmacodynamic biomarkers of activity. Gene expression data from pretreatment tumors showed that pts who progressed had a proportionally higher myeloid gene signature (eg, IL8, CCL2). Updated data will be presented, including data from PD-L1–neg pts. Conclusions: MPDL3280A was well tolerated in this pretreated UBC population. 50% of pts treated responded to treatment. Responses were rapid and on-going. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to therapy. Clinical trial information: NCT01375842.
Mechanisms of capacitative calcium entry (2001)

Capacitative Ca(2+) entry involves the regulation of plasma membrane Ca(2+) channels by the filling state of intracellular Ca(2+) stores in the endoplasmic reticulum (ER). Several theories have been advanced regarding the mechanism by which the stores communicate with the plasma membrane. One such mechanism, supported by recent findings, is conformational coupling: inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) receptors in the ER may sense the fall in Ca(2+) levels through Ca(2+)-binding sites on their lumenal domains, and convey this conformational information directly by physically interacting with Ca(2+) channels in the plasma membrane. In support of this idea, in some cell types, store-operated channels in excised membrane patches appear to depend on the presence of both Ins(1,4,5)P(3) and Ins(1,4,5)P(3) receptors for activity; in addition, inhibitors of Ins(1,4,5)P(3) production that either block phospholipase C or inhibit phosphatidylinositol 4-kinase can block capacitative Ca(2+) entry. However, the electrophysiological current underlying capacitative Ca(2+) entry is not blocked by an Ins(1,4,5)P(3) receptor antagonist, and the blocking effects of a phospholipase C inhibitor are not reversed by the intracellular application of Ins(1,4,5)P(3). Furthermore, cells whose Ins(1,4,5)P(3) receptor genes have been disrupted can nevertheless maintain their capability to activate capacitative Ca(2+) entry channels in response to store depletion. A tentative conclusion is that multiple mechanisms for signaling capacitative Ca(2+) entry may exist, and involve conformational coupling in some cell types and perhaps a diffusible signal in others.
Acetylcholine receptor pathway in lung cancer: New twists to an old story (2014)

Genome-wide association studies revealed that allelic variation in the α5-α3-β4 nicotine acetylcholine receptor (nAChR) cluster on chromosome 15q24-15q25.1 was associated with lung cancer risk. nAChRs are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine (ACh) or other biologic compounds including nicotine. nAChRs have been found on lung cancer cells, underscoring the idea that the non-neuronal nAChR pathway has important implications for lung cancer. Several studies focusing on the treatment with nAChR antagonists with improved selectivity might trigger novel strategies for the intervention and prevention of lung cancer. Here we review the genetic risk factors for lung cancer in the nAChR gene cluster, the roles of nicotine receptors, and the molecular mechanisms of acetylcholine receptor pathways to lead to more opportunities for intervention and prevention of lung cancer.
Numerical evaluation of effective dielectric properties of three-dimensional composite materials with arbitrary inclusions using a finite-difference time-domain method (2007)

In this article, we introduce a numerical procedure to evaluate effective dielectric properties of arbitrary multicomponent three-dimensional mixtures. Recognizing that many mixtures have periodic extend in all directions, we only need to analyze a unit element for effective electrical properties extraction. The numerical technique used here is a finite-difference time-domain method with a periodic boundary condition that generalizes many boundary conditions used in previous works. Several numerical examples are provided to demonstrate the effectiveness of this method. Using this developed procedure, we study the effects of frequency, inclusion shapes, inclusion volume, and inclusion conductivity on mixture’s electrical properties. It is observed that these parameters can significantly change the electrical properties of mixtures.
The Human Cathelicidin LL-37 Preferentially Promotes Apoptosis of Infected Airway Epithelium (2010)

Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.
A novel strategy for constructing N‐terminal chromosomal fusions to green fluorescent protein in the yeast Saccharomyces cerevisiae (2000)

A novel rapid polymerase chain reaction (PCR)-based technique for N-terminal attachment of green fluorescent protein (GFP) to a yeast protein is described. Genomic integration of a PCR-generated loxPkanMX4loxP-yEGFP fusion cassette immediately upstream of the open reading frame (ORF) allows for selection of G418 resistant transformants carrying GFP fused N-terminally to the protein of interest. In a subsequent step, the loxPkanMX4loxP selection marker that is inserted between the tagged ORF and the endogenous promoter is excised upon site-specific recombination between the loxP sites by Cre recombinase, leaving behind in the promoter one loxP site, immediately upstream of the GFP start codon. The essential protein Ydl193wp of unknown function and the oleate-inducible fatty acid activation protein, encoded by FAA2, were N-terminally tagged using the novel technique. Both experiments yielded viable haploid strains with growth phenotypes indistinguishable from the wild type strain. The subcellular localization pattern for the chromosomally expressed GFP-Ydl193wp to the endoplasmic reticulum and lipid particles was identical to the pattern observed for a plasmid-borne GFP construct expressed under control of the MET25(p) promoter, albeit at a lower level and with a more homogeneous distribution among the cell population. GFP-FAA2 was inducible by oleate, as is the wild type gene, demonstrating that specific expression patterns are not grossly affected by the promoter manipulation. In agreement with previous reports, GFP-Faa2p was found to localize to peroxisomes.
Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. (1992)

Disease-oriented panels of human tumor cell lines used by the National Cancer Institute for large-scale in vitro anticancer drug screening were evaluated for multidrug-resistant phenotype at the functional (in vitro drug sensitivity) and molecular levels. The cell line panels manifested a broad range of sensitivities to drugs typically associated with multidrug resistance (MDR) as well as to drugs not associated with MDR. Individual cell lines displayed unique and characteristic profiles of response. Patterns of correlated response were observed among, but not between, MDR and non-MDR drugs. Strong evidence of correlated response was limited to drugs sharing an intracellular mechanism of action. Several tumor cell lines exhibited a high degree of resistance to MDR drugs and relative sensitivity to non-MDR drugs, contained high levels of MDR-1 mRNA, and expressed cell surface P-glycoprotein detectable with one or more monoclonal antibodies. Parallel expression of all of these features representing the classic MDR phenotype was observed among members of the colon and renal tumor panels. Certain individual cell lines among other panels (lung, ovarian, melanoma, and central nervous system) also manifested some aspects of the MDR phenotype to various extents. Identification of MDR cell lines used for large-scale in vitro anticancer drug screening will facilitate interpretation of data in a way which may allow identification of new drug leads of potential value in treatment of MDR tumor cell populations.
Site-directed Mutagenesis of P2U Purinoceptors (1995)

Two subtypes of G protein-coupled receptors for nucleotides (P2U and P2Y purinoreceptors) contain several conserved positively charged amino acids in the third, sixth, and seventh putative transmembrane helices (TMHs). Since the fully ionized form of nucleotides has been shown to be an activating ligand for both P2U and P2Y purinoceptors (P2UR and P2YR), we postulated that some of these positively charged amino acids are involved in binding of the negatively charged phosphate groups of nucleotides. To investigate the role of the conserved positively charged amino acids in purinoceptor function, a series of mutant P2UR cDNAs were constructed so that lysine 107 and arginine 110 in TMH 3, histidine 262 and arginine 265 in TMH 6, and arginine 292 in TMH 7 were changed to the neutral amino acid leucine or isoleucine. The mutated P2UR cDNAs were stably expressed in 1321N1 astrocytoma cells and receptor activity was monitored by quantitating changes in the concentration of intracellular Ca2+ upon stimulation with full (ATP, UTP) or partial (ADP, UDP) P2UR agonists. Neutralization of His262, Arg265, or Arg292 caused a 100-850-fold decrease in the potency of ATP and UTP relative to the unmutated P2UR and rendered ADP and UDP ineffective. In contrast, neutralization of Lys107 or Arg110 did not alter the agonist potency or specificity of the P2UR. Neutralization of Lys289 in the P2UR, which is expressed as a glutamine residue in the P2Y subtype, did not alter receptor activity; however, a conservative change from lysine to arginine at this position altered the rank order of agonist potency so that ADP and UDP were approximately 100-fold more potent than ATP and UTP. A three-dimensional model of the P2UR indicates the feasibility of His262, Arg265, and Arg292 interactions with the phosphate groups of nucleotides.
Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. (1999)

Whereas signal transducers and activators of transcription were originally discovered as mediators of normal cytokine signaling, constitutive activation of certain signal transducer and activator of transcription proteins, including Stat3, has been found in increasing numbers of human cancers. Recently, a causal role for Stat3 activation in oncogenesis has been demonstrated, suggesting that Stat3 represents a novel target for cancer therapy. We report here that in vitro expression of a Stat3 variant with dominant-negative properties, Stat3beta, induced cell death in murine B16 melanoma cells that harbored activated Stat3. By contrast, expression of Stat3beta had no effect on normal fibroblasts or the Stat3-negative murine tumor MethA, suggesting that only tumor cells with activated Stat3 have become dependent on this pathway for survival. Significantly, gene therapy by electroinjection of the Stat3beta expression vector into preexisting B16 tumors caused inhibition of tumor growth as well as tumor regression. This Stat3beta-induced antitumor effect is associated with apoptosis of the B16 tumor cells in vivo. These findings demonstrate for the first time that interfering with Stat3 signaling induces potent antitumor activity in vivo and thus identify Stat3 as a potential molecular target for therapy of human cancers harboring activated Stat3.
A statistical inference based growth criterion for the RBF network (2002)

In this paper, a growth criterion is derived using statistical inference for model sufficiency. This criterion is developed for recursive estimation or sequential learning with neural networks. A growing Gaussian radial basis function (GaRBF) network trained by the extended Kalman filter (EKF) algorithm on-line, called incremental network is developed. Incremental network is similar to the resource allocating network (RAN). The criterion for growth is based on the network prediction error and the expected uncertainty in the network output. The criterion is computed within the EKF estimation end hence no additional computations are required. This is in contrast to the need for search in the RAN formulation. The incremental network performance on a function interpolation problem is shown to be superior in convergence speed and approximation accuracy than the RAN networks and a fixed size RBF network.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Application of a membrane model to the sorptive interactions of humic substances. (1989)

Humic substances, the dark-colored, natural organic polyelectrolytes that are found in practically all soils, sediments, and natural water, strongly interact with both inorganic and organic pollutants. Inorganic cationic species generally undergo complexation reactions with humic substances. The binding of cations, such as cupric ions, by humic substances often markedly reduces their toxicity to aquatic organisms. Some inorganic anionic species, in the presence of metal ions, are sorbed by humic substances. In these instances the metal ions appear to form bridges between the humic substances and the anions. Several different types of interactions take place between organic compounds and humic materials. Hydrophobic organic species partition into either insoluble or soluble humic substances. The insoluble humic substances will remove hydrophobic organic compounds from the aqueous phase, thereby rendering them less mobile. However, soluble humic substances will solubilize hydrophobic organics, increasing their mobility. Other types of interactions between humic substances and organic compounds, such as adsorption and ion exchange, also have been observed. These various interactions between humic substances and pollutants are important in governing their fate and movement in natural water systems, and, for this reason, a detailed understanding of the mechanisms of the interaction is important. A recently developed membrane model of the structure of humic substances is described; this model enables one to better understand the physical-chemical properties of these materials.
Tabbycat: an inexpensive scalable server for video-on-demand (2004)

Tabbycat is a video server prototype demonstrating the benefits of a proactive approach for distributing popular videos on demand to a large customer base. Rather than reacting to individual customer requests, Tabbycat broadcasts the contents of the most popular videos according to a fixed schedule. As a result, the number of customers watching a given video does not affect the cost of distributing it. We found that one workstation with a single ATA disk drive and a fast Ethernet interface could distribute three two-hour videos while achieving a maximum customer waiting time of less than four minutes.