gebhart/patrepeval huggingface dataset:
Inhibition of Sendai virus genome replication due to promoter-increased selectivity: a possible role for the accessory C proteins (1997)

The role of the negative-stranded virus accessory C proteins is difficult to assess because they appear sometimes as nonessential and thereby of no function. On the other hand, when a function is found, as in the case of Sendai virus, it represents an enigma, in that the C proteins inhibit replication under conditions where the infection follows an exponential course. Furthermore, this inhibitory function is exerted differentially: in contrast to the replication of internal deletion defective interfering (DI) RNAs, that of copy-back DI RNAs appears to escape inhibition, under certain experimental conditions (in vivo assay). In a reexamination of the C effect by the reverse genetics approach, it was found that copy-back RNA replication is inhibited by C in vivo as well, under conditions where the ratio of C to copy-back template is increased. This effect can be reversed by an increase in P but not L protein. The "rule of six" was differentially observed in the presence or absence of C. Finally, a difference in the ability of the replicating complex to tolerate promoter modifications in RNA synthesis initiation was shown to occur in the presence or the absence of C as well. We propose that C acts by increasing the selectivity of the replicating complex for the promoter cis-acting elements governing its activity. The inhibitory effect of C becomes the price to pay for this increased selectivity.
Targeting the EGFR/PCNA Signaling Suppresses Tumor Growth of Triple-Negative Breast Cancer Cells with Cell-Penetrating PCNA Peptides (2013)

Tyrosine 211 (Y211) phosphorylation of proliferation cell nuclear antigen (PCNA) coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant cells, both nuclear EGFR (nEGFR) expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC). Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP) inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA in vivo; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP), which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.
HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway (2006)

Genetic deficiency or inhibition of cholesteryl ester transfer protein (CETP) leads to a marked increase in plasma levels of large HDL-2 particles. However, there is concern that such particles may be dysfunctional in terms of their ability to promote cholesterol efflux from macrophages. Recently, the ATP-binding cassette transporter ABCG1, a macrophage liver X receptor (LXR) target, has been shown to stimulate cholesterol efflux to HDL. We have assessed the ability of HDL from subjects with homozygous deficiency of CETP (CETP-D) to promote cholesterol efflux from macrophages and have evaluated the role of ABCG1 and other factors in this process. CETP-D HDL-2 caused a 2- to 3-fold stimulation of net cholesterol efflux compared with control HDL-2 in LXR-activated macrophages, due primarily to an increase in lecithin:cholesterol acyltransferase-mediated (LCAT-mediated) cholesteryl ester formation in media. Genetic knockdown or overexpression of ABCG1 showed that increased cholesterol efflux to CETP-D HDL was ABCG1 dependent. LCAT and apoE contents of CETP-D HDL-2 were markedly increased compared with control HDL-2, and increased cholesterol esterification activity resided within the apoE-HDL fraction. Thus, CETP-D HDL has enhanced ability to promote cholesterol efflux from foam cells in an ABCG1-dependent pathway due to an increased content of LCAT and apoE.
Comment on “Low-loss terahertz ribbon waveguides” (2008)

We point out an important fundamental limitation associated with the dielectric ribbon waveguide described by Yeh [Appl. Opt.44, 5937 (2005)], which would restrict its practical use in ultrahigh- or terahertz-speed guided-wave applications, contrary to their underlying prediction, and we additionally point out a noteworthy inaccuracy in their introductory discussion.
Polo‐like kinase (Plk) 1: a novel target for the treatment of prostate cancer (2004)

Second only to skin cancer, cancer of the prostate gland (CaP) is the most commonly occurring cancer in American men. Existing treatment approaches and surgical intervention have been unable to effectively manage this dreaded cancer; therefore, efforts are ongoing to explore novel targets and strategies for the management of CaP. A complete understanding of the genetic control of the processes of cellular proliferation and programmed cell death, or "apoptosis," may provide the basis for the rational design of novel therapeutic strategies against CaP. Key regulators for the mitotic progression in mammalian cells are the polo-like kinases (Plks). The activity of Plk1 is elevated in tissues and cells with a high mitotic index, including cancer cells. An increasing body of evidence suggests that the level of Plk1 expression has prognostic value for predicting outcomes in patients with some cancers such as lung cancer, squamous cell carcinomas of the head and neck, melanomas, and ovarian and endometrial carcinomas. However, the role of Plk1 in CaP is not known. Here, a hypothesis is put forward that Plk 1 plays a critical role in the development of prostate cancer; and the silencing of Plk1 will result in elimination of human CaP cells via an inactivation of cyclin-dependent kinase 1 (Cdc2)/cyclin B 1-mediated mitotic arrest followed by apoptosis. A corollary to this hypothesis is that Plk1 could serve as a target for the intervention of CaP in humans. Therefore, if the hypothesis is tested to be true, it is conceivable that gene therapeutic approaches aimed at Plk1 or the pharmacological inhibitors of Plk1 may be developed for the treatment/management of CaP.
Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance (2005)

Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause resistance to the ABL kinase inhibitor imatinib by impairing the flexibility of the kinase domain, restricting its ability to adopt the inactive conformation required for optimal imatinib binding, rather than by directly interfering with drug contact residues. BMS-354825, currently in clinical development for imatinib-resistant chronic myelogenous leukemia, is a dual SRC/ABL kinase inhibitor that binds ABL in both the active and inactive conformation. To examine the potential role of conformational binding properties in drug resistance, we mapped the mutations in BCR-ABL capable of conferring resistance to BMS-354825. Through saturation mutagenesis, we identified 10 such BCR-ABL mutations, 8 of which occurred at drug contact residues. Some mutants were unique to BMS-354825, whereas others also conferred imatinib resistance. Remarkably, the identity of the amino acid substitution at either of two contact residues differentially affects sensitivity to imatinib or BMS-354825. The combination of imatinib plus BMS-354825 greatly reduced the recovery of drug-resistant clones. Our findings provide further rationale for considering kinase conformation in the design of kinase inhibitors against cancer targets.
Chloride Inclusion and Hole Transport Material Doping to Improve Methyl Ammonium Lead Bromide Perovskite-Based High Open-Circuit Voltage Solar Cells (2014)

Low-cost solar cells with high VOC, relatively small (EG - qVOC), and high qVOC/EG ratio, where EG is the absorber band gap, are long sought after, especially for use in tandem cells or other systems with spectral splitting. We report a significant improvement in CH3NH3PbBr3-based cells, using CH3NH3PbBr3-xClx, with EG = 2.3 eV, as the absorber in a mesoporous p-i-n device configuration. By p-doping an organic hole transport material with a deep HOMO level and wide band gap to reduce recombination, the cell's VOC increased to 1.5 V, a 0.2 V increase from our earlier results with the pristine Br analogue with an identical band gap. At the same time, in the most efficient devices, the current density increased from ∼1 to ∼4 mA/cm(2).
Minimally Invasive Pervaginam Procedures for the Treatment of Female Stress Incontinence Using a New Pubic Bone Anchoring System (1998)

The purpose of this ongoing study is to evaluate the safety and efficacy of new minimally invasive pervaginam cystourethropexy and sling procedures for the treatment of female genuine stress urinary incontinence. A total of 75 women (mean age, 52.8 years) underwent either a cystourethropexy or a sling procedure. A miniature bone anchor and a staple-like bone anchor driver were used for the fixation of periurethral tissue or a xenogenic sling to the pubic bone. With a mean follow-up of eight months, 61 patients (82%) were completely cured of stress incontinence, 10 (14%) reported a more than 50% decrease in pad usage, and 4 patients showed failure early following surgery. The exclusively pervaginam cystourethropexy and sling procedures are minimally invasive, safe, and effective. Further experience and longer follow-up are necessary to establish their role in the treatment of women with stress urinary incontinence.
Differential Palmit(e)oylation of Wnt1 on C93 and S224 Residues Has Overlapping and Distinct Consequences (2011)

Though the mechanisms by which cytosolic/intracellular proteins are regulated by the post-translational addition of palmitate adducts is well understood, little is known about how this lipid modification affects secreted ligands, such as Wnts. Here we use mutational analysis to show that differential modification of the two known palmit(e)oylated residues of Wnt1, C93 and S224, has both overlapping and distinct consequences. Though the relative roles of each residue are similar with respect to stability and secretion, two distinct biological assays in L cells show that modification of C93 primarily modulates signaling via a ß-catenin independent pathway while S224 is crucial for ß-catenin dependent signaling. In addition, pharmacological inhibition of Porcupine (Porcn), an upstream regulator of Wnt, by IWP1, specifically inhibited ß-catenin dependent signaling. Consistent with these observations, mapping of amino acids in peptide domains containing C93 and S224 demonstrate that acylation of C93 is likely to be Porcn-independent while that of S224 is Porcn-dependent. Cumulatively, our data strongly suggest that C93 and S224 are modified by distinct enzymes and that the differential modification of these sites has the potential to influence Wnt signaling pathway choice.
Antibacterial activity and biofilm inhibition by surface modified titanium alloy medical implants following application of silver, titanium dioxide and hydroxyapatite nanocoatings (2017)

One of the most common causes of implant failure is peri-implantitis, which is caused by bacterial biofilm formation on the surfaces of dental implants. Modification of the surface nanotopography has been suggested to affect bacterial adherence to implants. Silver nanoparticles are also known for their antibacterial properties. In this study, titanium alloy implants were surface modified following silver plating, anodisation and sintering techniques to create a combination of silver, titanium dioxide and hydroxyapatite (HA) nanocoatings. Their antibacterial performance was quantitatively assessed by measuring the growth of Streptococcus sanguinis, proportion of live/dead cells and lactate production by the microbes over 24 h. Application of a dual layered silver-HA nanocoating to the surface of implants successfully inhibited bacterial growth in the surrounding media (100% mortality), whereas the formation of bacterial biofilm on the implant surfaces was reduced by 97.5%. Uncoated controls and titanium dioxide nanocoatings showed no antibacterial effect. Both silver and HA nanocoatings were found to be very stable in biological fluids with material loss, as a result of dissolution, to be less than 0.07% for the silver nanocoatings after 24 h in a modified Krebs-Ringer bicarbonate buffer. No dissolution was detected for the HA nanocoatings. Thus, application of a dual layered silver-HA nanocoating to titanium alloy implants creates a surface with antibiofilm properties without compromising the HA biocompatibility required for successful osseointegration and accelerated bone healing.
Molecular cloning and sequencing of an operon, carRS of Azospirillum brasilense, that codes for a novel two-component regulatory system: demonstration of a positive regulatory role of carR for global control of carbohydrate catabolism (1994)

A pleiotropic carbohydrate mutant, CR17, of Azospirillum brasilense RG (wild type) that assimilates C4 dicarboxylates (succinate and malate) but not carbohydrate (fructose, arabinose, galactose, glycerol, and gluconate) as C sources for growth was used to identify the car (carbohydrate regulation) locus by complementation analysis. The 2.8-kb genomic fragment that complemented the Car- defect of CR17 and overlapped the fru operon (S. Chattopadhyay, A. Mukherjee, and S. Ghosh, J. Bacteriol. 175:3240-3243, 1993) has now been completely sequenced. The sequence contains an operon, carRS, coding for two proteins, CARR and CARS, having 236 and 352 amino acid residues, respectively. The 3'-flanking region of the carRS operon showed sequence homology with the 5' terminus of the fruB gene of a related bacterium, Rhodobacter capsulatus. A complementation study with carRS deletion clones showed that only the carR+ gene was required to complement the Car- defect of CR17, signifying that the carbohydrate pleiotropy was due to a lesion within this gene. Although the 2.8-kb DNA containing the carRS operon when introduced by conjugation into CR17 also complemented the Car- defect, the complemented transconjugant was unable to utilize succinate as a C source. The reason for this is not clear. A sequence analysis of the two protein products strongly suggests that the protein pair may constitute a novel two-component regulatory system for global expression of carbohydrate catabolic pathways in A. brasilense.
Epidemiological and clinical characteristics of cutaneous leishmaniasis and their relationship with the laboratory data, south of Brazil (2011)

Findings suggest that for the adequate identification of ACL cases a combination of laboratory tests that involves the association of MST with at least another test should be used.
Chemical Basis for the Affinity Maturation of a Camel Single Domain Antibody (2004)

Affinity maturation of classic antibodies supposedly proceeds through the pre-organization of the reactive germ line conformational isomer. It is less evident to foresee how this can be accomplished by camelid heavy-chain antibodies lacking light chains. Although these antibodies are subjected to somatic hypermutation, their antigen-binding fragment consists of a single domain with restricted flexibility in favor of binding energy. An antigen-binding domain derived from a dromedary heavy-chain antibody, cAb-Lys3, accumulated five amino acid substitutions in CDR1 and CDR2 upon maturation against lysozyme. Three of these residues have hydrophobic side chains, replacing serines, and participate in the hydrophobic core of the CDR1 in the mature antibody, suggesting that conformational rearrangements might occur in this loop during maturation. However, transition state analysis of the binding kinetics of mature cAb-Lys3 and germ line variants show that the maturation of this antibody relies on events late in the reaction pathway. This is reflected by a limited perturbation of k(a) and a significantly decreased k(d) upon maturation. In addition, binding reactions and the maturation event are predominantly enthalpically driven. Therefore, maturation proceeds through the increase of favorable binding interactions, or by the reduction of the enthalpic penalty for desolvation, as opposed to large entropic penalties associated with conformational changes and structural plasticity. Furthermore, the crystal structure of the mutant with a restored germ line CDR2 sequence illustrates that the matured hydrophobic core of CDR1 in cAb-Lys3 might be compensated in the germ line precursor by burying solvent molecules engaged in a stable hydrogen-bonding network with CDR1 and CDR2.
The Interaction of Clostridium perfringens and Its Toxins in the Production of Necrotic Enteritis of Chickens (1977)

The intraduodenal administration of large numbers of Clostridium perfringens cells harvested from broth cultures and resuspended in PBS or fresh sterile thioglycollate broth produced a very mild form of necrotic enteritis. Administering an appropriate number of cells in culture supernatant, however, produced typical field-type disease. Alpha toxin was shown to be the significant toxin recoverable from broth-culture supernatant fluids. Requirements to produce the disease are minor intestinal damage and sufficient numbers of toxigenic C. perfringens in the intestine.
Electron Transfer Reactions in Pulping Systems (II): Electrochemistry of Anthraquinone/Lignin Model Quinonemethides (1985)

Abstract Electron transfer reactions have been observed during the electrolyses of solutions containing anthraquinone and 8-aryl ether lignin model quinonemethides. In dry acetonitrile at a reduction potential of -0.9V (vs. Ag/AgCl) electrons are transferred from the electrode to anthraquinone (AQ) to form stable anthrahydroquinone radical anions (AHQ−). The lignin model quinonemethides are not reduced directly at the electrode at this potential but are reduced by AHQ− to give quinonemethide radical anions (QM−) and AQ. The QM− species rapidly fragment at their β-aryl ether bond to give phenolate ions and radicals; the latter further reduces to another phenolate ion. For example, the β-methyl lignin model QM 1 gives guaiacol and isoeugenol upon electrolysis at -0.9V in the presence of AQ. In wet acetonitrile, reduction of AQ at -0.9V leads to both anthrahydroquinone radical anion and dianion; the dianion is formed by direct electrolysis of the radical anion and by disproportlonation of the radical anion. Under all conditions and substrates examined, electron transfer reactions proceeded in preference to bond formation reactions which would generate “adducts.” The implication of these results Is that it should be possible to delignlfy wood by electron transfer reactions and that anthraquinone probably functions this way.
Methionine Biosynthesis in Brevibacterium flavum: Properties and Essential Role of O-Acetylhomoserine Sulfhydrylase (1982)

Out of 27 strains of methionine auxotrophs of Brevibacterium flavum, 14 strains did not grow on homoserine but grew on O-acetylhomoserine, and all were found to lack homoserine O-acetyltransferase [EC 2.3.1.31] alone. Another 3 strains did not grow on O-acetylhomoserine but grew on homocysteine, and the two strains tested were found to lack O-acetylhomoserine sulfhydrylase (AHS) alone, without any changes in the activities of cystathionine gamma-synthase [EC4.2.99.9] and beta-cystathionase [EC 4.4.1.8]. Prototrophic revertants of the AHS-lacking mutants showed concomitant reversion of AHS activity. None of the methionine auxotrophs grew on cystathionine. From these results it was concluded that the methionine biosynthetic pathway of this bacterium involves formation of O-acetylhomoserine from homoserine by the action of homoserine O-acetyltransferase, and direct formation of homocysteine from O-acetylhomoserine by the AHS reaction. AHS synthesis was strongly repressed by methionine. AHS was purified to 70% purity. The purified preparation was activated by pyridoxal phosphate after treatment with hydroxylamine. The enzyme showed a molecular weight of 360,000, an optimum pH of 8.7 for activity, and specifically reacted with O-acetyl-L-homoserine and showed with O-acetyl-L-serine one hundredth as much activity as that with O-acetylo -homoserine, but did not show activity with O-succinyl-L-homoserine, homoserine, or serine. The Km values for O-acetylhomoserine and H2S were 2.0 mM and 0.08 mM, respectively. The enzyme was inhibited 50, 23. and 29% by 10 mM L-methionine, l-homoserine, and O-acetyl-L-serine, respectively, but it was not inhibited by cystathionine or S-adenosyl-L-methionine.
Precision Hand Assembly of MEMS Subsystems Using DRIE-Patterned Deflection Spring Structures: An Example of an Out-of-Plane Substrate Assembly (2007)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> This paper describes a packaging concept for precise hand-assembly of microelectromechanical systems (MEMS) subsystems that uses mesoscaled deep-reactive ion etching (DRIE) patterned passive deflection spring clusters. The method is intended for applications that require decoupling of subsystem process flows to simplify device fabrication in order to attain macro three-dimensionality, or for cases where the device requires spatially referenced macro- and microfeatures with good precision. The design considerations for the deflection springs are presented, and a simple reduced-order model of the expected elastic behavior is proposed. The assembly concept is demonstrated with an electrospray array test structure. This test structure assembles perpendicularly two wafer substrates. The performance of the test structure is benchmarked using finite-element simulations and by measurements of the misalignment introduced by the assembly. A floor for the ultimate alignment accuracy of the assembly concept is proposed. <papernumber>1456</papernumber> </para>
The mast cell. (1981)

The mast cell is the cellular basis for immediate hypersensitivity reactions. The specificity of the immediate hypersensitivity reaction is attributable to IgE molecules fixed to specific membrane receptors which, when stimulated by specific antigen, initiates the process of degranulation of the mast cell. The granules provide three separate sources of biologic activity: performed or primary mediators, newly generated or secondary mediators, and activities associated with the granular matrix. A number of biologic consequences are generated in response to these mediators and these include: increased vascular permeability, vasodilation, smooth muscle spasm, polymorphonuclear leukocyte chemotaxis, stimulation of adenylate and guanylate cyclase, superoxide radical generation, prostaglandin formation, mucous and gastric acid secretion, hypotension, tissue destruction, and mononuclear leukocyte infiltration. This pharmacopia of activities accounts for the clinical aspects of allergic diseases, suggests that the mast cell granule may be involved in the host's defense against parasitic infections, and is compatible with a suggested role of the mast cell as a widely distributed, monocellular endocrine system.