gebhart/patrepeval huggingface dataset:
Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1 (2005)

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5'-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.
Mechanical Properties of Cross-Linked Synthetic Elastomeric Polypentapeptides (2001)

Mechanical properties in equilibrium swelling states were examined for two elastomeric polypentapeptides, namely, (GVGVP)251 and (GVGIP)260 where G = glycine, V = valine, P = proline, and I = isoleucine. They had been prepared using recombinant DNA technology and cross-linked by γ-irradiation over the range of doses from 6 to 30 Mrad. Moduli were measured in uniaxial tensile tests. The specific work of fracture was determined as a measure of toughness. Increased doses of γ-radiation increased the moduli (cross-link density) of hydrogels. The hydrophobic folding and assembly phase transition that occurred on raising the temperature was demonstrated to have significant effects on moduli and fracture properties. Thermoelasticity experiments suggest that the phase transition involves changes in elasticity mechanism. Above the transition temperature, hydrogels were shown to become more viscoelastic.
The generation of endostatin is mediated by elastase. (1999)

Endostatin, a potent inhibitor of angiogenesis and tumor growth, is a COOH-terminal fragment of collagen XVIII derived through cleavage of an Ala-His linkage by an as yet unidentified endostatin-processing enzyme. Endostatin was originally isolated from the conditioned medium of hemangioendothelioma (EOMA) cells. By investigating the processing of collagen XVIII to endostatin by EOMA cells, we show here that the generation of endostatin can be mediated by an elastase activity. We also show that several members of the elastase family can act as an endostatin-processing enzyme by specifically cleaving the Ala-His linkage and releasing endostatin from a precursor molecule. We further suggest that the generation of endostatin from collagen XVIII is at least a two-step process, involving a metal-dependent early step and an elastase activity-dependent final step.
GCN5 is a required cofactor for a ubiquitin ligase that targets NF-κB/RelA (2009)

The transcription factor NF-kappaB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-kappaB subunits plays an important role in the termination of NF-kappaB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses kappaB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IkappaB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.
WD‐repeat‐propeller‐FYVE protein, ProF, binds VAMP2 and protein kinase Cζ (2007)

We have recently identified a protein, consisting of seven WD repeats, presumably forming a beta-propeller, and a domain identified in Fab1p, YOTB, VAC1p, and EEA1 (FYVE) domain, ProF. The FYVE domain targets the protein to vesicular membranes, while the WD repeats allow binding of the activated kinases Akt and protein kinase (PK)Czeta. Here, we describe the vesicle-associated membrane protein 2 (VAMP2) as interaction partner of ProF. The interaction is demonstrated with overexpressed and endogenous proteins in mammalian cells. ProF and VAMP2 partially colocalize on vesicular structures with PKCzeta and the proteins form a ternary complex. VAMP2 can be phosphorylated by activated PKCzeta in vitro and the presence of ProF increases the PKCzeta-dependent phosphorylation of VAMP2 in vitro. ProF is an adaptor protein that brings together a kinase with its substrate. VAMP2 is known to regulate docking and fusion of vesicles and to play a role in targeting vesicles to the plasma membrane. The complex may be involved in vesicle cycling in various secretory pathways.
Bone: Formation by Autoinduction (1965)

Wandering histiocytes, foreign body giant cells, and inflammatory connective-tissue cells are stimulated by degradation products of dead matrix to grow in and repopulate the area of an implant of decalcified bone. Histiocytes are more numerous than any other cell form and may transfer collagenolytic activity to the substrate to cause dissolution of the matrix. The process is followed immediately by new-bone formation by autoinduction in which both the inductor cells and the induced cells are derived from ingrowing cells of the host bed. The inductor cell is a descendant of a wandering histiocyte; the induced cell is a fixed histiocyte or perivascular young connective-tissue cell. Differentiation of the osteoprogenitor cell is elicited by local alterations in cell metabolic cycles that are as yet uncharacterized.
Evaluation of Anti-HSV-2 Activity of Gallic Acid and Pentyl Gallate (2008)

The synthetic n-alkyl esters of gallic acid, also known as gallates, are widely employed as antioxidants by food and pharmaceutical industries. Besides the antioxidant activity, other biological activities have been described for this group of molecules, mainly anticancer, antibacterial and antifungal properties. In the present study, the anti-herpes simplex virus (HSV)-2 activity of gallic acid and pentyl gallate was evaluated followed by the determination of the site of antiviral activity of these compounds. Our results demonstrated that both compounds reduced HSV-2 replication in a concentration-dependent manner when either incubated with the virus prior to the addition of the mixture to cells, or added to and incubated with cells after their infection. In summary, the anti-HSV-2 activity of gallic acid and pentyl gallate was ascribed to their virucidal effect on virus particles, a change that was likely accompanied by partial inhibition of the virus attachment to cells and its subsequent cell-to-cell spread activity. This suggests that these compounds can be regarded as promising candidates for development as topical anti-HSV-2 agents.
The miRNAs and Epithelial-Mesenchymal Transition in Cancers (2014)

The epithelial-mesenchymal transition (EMT) is a process by which epithelial tumor cells acquire migratory and invasive abilities that enable them to spread to other organs. During this process, the tight junction molecule, E-cadherin, is often downregulated through transcription repression by the EMT-inducing transcription factors (EMT-TFs). MicroRNAs (miRNAs) are a class of small noncoding RNA molecules which bind to the complementary sequences within mRNA molecules. They post-transcriptionally govern gene silencing, thus affecting a broad range of physiological conditions, including EMT. In this review, we will discuss some well-known as well as brand-new EMT-related miRNAs and the signaling pathways in the tumor milieu that regulate their expressions and control cancer invasion and metastasis. Finally, we will discuss the application of miRNAs as therapeutic targets for treatment of cancer.
Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. (1989)

Using mAb technology (Wayner, E. A., W. G. Carter, R. Piotrowicz, and T. J. Kunicki. 1988. J. Cell Biol. 107:1881-1891), we have identified a new fibronectin receptor that is identical to the integrin receptor alpha 4 beta 1. mAbs P3E3, P4C2, and P4G9 recognized epitopes on the alpha 4 subunit and completely inhibited the adhesion of peripheral blood and cultured T lymphocytes to a 38-kD tryptic fragment of plasma fibronectin containing the carboxy-terminal Heparin II domain and part of the type III connecting segment (IIICS). The ligand in IIICS for alpha 4 beta 1 was the CS-1 region previously defined as an adhesion site for melanoma cells. The functionally defined mAbs to alpha 4 partially inhibited T lymphocyte adhesion to intact plasma fibronectin and had no effect on their attachment to an 80-kD tryptic fragment containing the RGD (arg-gly-asp) adhesion sequence. mAbs (P1D6 and P1F8) to the previously described fibronectin receptor, alpha 5 beta 1, completely inhibited T lymphocyte adhesion to the 80-kD fragment but had no effect on their attachment to the 38-kD fragment or to CS-1. Both alpha 4 beta 1 and alpha 5 beta 1 localized to focal adhesions when fibroblasts that express these receptors were grown on fibronectin-coated surfaces. These findings demonstrated a specific interaction of both receptors with fibronectin at focal contacts. In conclusion, these findings show clearly that cultured T lymphocytes use two independent receptors during attachment to fibronectin and that (a) alpha 5 beta 1 is the receptor for the RGD containing cell adhesion domain, and (b) alpha 4 beta 1 is the receptor for a carboxy-terminal cell adhesion region containing the Heparin II and IIICS domains. Furthermore, these data also show that T lymphocytes express a clear preference for a region of molecular heterogeneity in IIICS (CS-1) generated by alternative splicing of fibronectin pre-mRNA and that alpha 4 beta 1 is the receptor for this adhesion site.
Fabrication of a magnet‐assisted alignment device for the amperometric detection of capillary electrophoresis using a carbon nanotube/polypropylene composite electrode (2012)

A magnet-assisted alignment device was designed and fabricated for the amperometric detection of CE. It mainly consisted of a magnet-containing electrode holder, a capillary-based microdisc detection electrode, a detection cell, and a micrometer adjuster. To demonstrate the feasibility and performance of the alignment device, it was used in combination with a carbon nanotube/polypropylene (CNT/PP) composite electrode for the determination of p-phenylenediamine, m-aminophenol, and m-dihydroxybenzene in commercial hair dye by CE. The CNT-based electrode was fabricated by packing a melt mixture of CNTs and PP in a piece of fused silica capillary under heat, offering significantly lower operating potentials, substantially enhanced signal-to-noise characteristics, and high resistance to surface fouling. Because magnetic force was employed to move the detection electrode, the alignment system was significantly simplified. It is characterized by simple design and fabrication, high alignment reproducibility, reduced alignment time, and low cost. Both the alignment device and the CNT/PP composite electrode should find a wide range of applications in microchip CE, flowing injection analysis, and other microfluidic analysis systems.
Non-Analgesic Effects of Opioids: Opioid-induced Nausea and Vomiting: Mechanisms and Strategies for their Limitation (2012)

Nausea and vomiting are common gastrointestinal symptoms following opioid administration, for either chronic or acute pain management. As a consequence, patients' dissatisfaction has a negative impact on treatment efficacy. A number of mechanisms have been identified, involving both central and peripheral sites. This article will review the pathophysiology of opioid-induced nausea and vomiting and the various pharmacological treatments currently available for its management. Preventive strategies and therapeutic approaches are evaluated in the perioperative setting and in chronic pain. Newer drugs include second generation serotonin receptor antagonists (palonosetron) and neurokinin-1 (NK-1) antagonists (aprepitant).
Efficient Generation of NKX6-1+ Pancreatic Progenitors from Multiple Human Pluripotent Stem Cell Lines (2015)

Human pluripotent stem cells (hPSCs) represent a renewable source of pancreatic beta cells for both basic research and therapeutic applications. Given this outstanding potential, significant efforts have been made to identify the signaling pathways that regulate pancreatic development in hPSC differentiation cultures. In this study, we demonstrate that the combination of epidermal growth factor (EGF) and nicotinamide signaling induces the generation of NKX6-1(+) progenitors from all hPSC lines tested. Furthermore, we show that the size of the NKX6-1(+) population is regulated by the duration of treatment with retinoic acid, fibroblast growth factor 10 (FGF10), and inhibitors of bone morphogenetic protein (BMP) and hedgehog signaling pathways. When transplanted into NOD scid gamma (NSG) recipients, these progenitors differentiate to give rise to exocrine and endocrine cells, including monohormonal insulin(+) cells. Together, these findings provide an efficient and reproducible strategy for generating highly enriched populations of hPSC-derived beta cell progenitors for studies aimed at further characterizing their developmental potential in vivo and deciphering the pathways that regulate their maturation in vitro.
Synaptogenesis of cultured striatal neurons in serum-free medium: a morphological and biochemical study. (1986)

Striatal neurons were cultured from the fetal mouse brain and maintained in serum-free medium for 14-21 days in vitro (DIV). Pretreatment of the culture dishes successively with a polycation followed by fetal calf serum resulted in rapid neuron attachment and neurite proliferation. After 9-10 DIV, electron microscope observations revealed the presence of vesicles in axon terminals forming mature synapses with axons and perikarya of adjacent neurons and in varicosities along extended axons. Synapsin I, a synaptic vesicle-specific protein, was present only in neuronal perikarya after 3 DIV, in perikarya and in varicosities along extended axons after 6 DIV, and in varicosities and contact points between axon terminals and adjacent axons or perikarya after 11-14 DIV. Neurotransmitter-stimulated intracellular formation of cAMP decreased markedly during neuronal differentiation. Inositol phosphate formation in response to neurotransmitters, however, increased significantly throughout the period of striatal neuronal development. K+ (56 mM) depolarization resulted in a 2-fold increase in endogenous gamma-aminobutyric acid (GABA) release from striatal neurons, 50% of which was Ca2+-dependent, between 3 and 11 DIV. Between 11 and 14 DIV, subsequent to synapse formation (as revealed by electron microscope observations), GABA release evoked by 56 mM K+ increased up to 5-fold, 75% of which was Ca2+-dependent. It appears that the complete differentiation of striatal neurons in serum-free medium may provide a suitable model for the study of the physiological and regulatory mechanisms involved in nerve cell development.
A rapid method for the measurement ofLeucaena spp proanthocyanidins by the proanthocyanidin (butanol/HCl) assay (1998)

Proanthocyanidin (PA) extraction, sample preparation and proanthocyanidin assay (butanol/HCl) reaction conditions were evaluated for measuring PA in Leucaena spp leaf material. The optimal conditions for extracting PA from leaf tissue are described, with short sequential sonications in 70% aqueous acetone being as efficient as prolonged sequential mechanical agitation. In methanol–based extracts, after back extraction to remove pigments, increasing the water content of the reagent/sample matrix suppressed colour development. The addition of low concentrations of Fe3+ to the butanol/HCl reagent enhanced colour yield, but higher Fe3+ concentrations suppressed colour development. The presence of ascorbic acid in the sample extract was shown to increase colour development. Varying the reagent: sample extract ratio from 4:1 to 6:1 significantly decreased colour yield, but neither ratio was different from 5:1. Optimum conditions for the PA assay were as follows: a water content of 8%, the omission of Fe3+, a reagent: sample extract ratio of 5:1 and the addition of ascorbic acid to the stock PA standard solution to match that contributed by the extract in the final mixture. Sample preparation procedures, using back extraction to remove pigments and non-PA phenolics with diethyl ether and ethyl acetate, respectively, were time-consuming and subject to PA losses. The measurement of PA directly in the 70% aqueous acetone extract eliminated these PA losses, but the PA assay required additional optimisation for direct analysis of crude acetone extracts. In the final optimised procedure, PA was extracted by sequential sonication with 70% aqueous acetone containing 5·26 mM sodium metabisulphite as the antioxidant. These extracts were directly analysed by the butanol/HCl reaction using a reagent: sample extract ratio of 5:1, the omission of Fe3+ from the butanol/HCl reagent and the addition of sodium metabisulphite to match that contributed by the extract. This produced consistent linear calibration curves over the range 25–1000 μg PA with an average recovery of 101%. © 1998 Society of Chemical Industry.
Genetics of the large, external, transformation-sensitive (LETS) protein: assignment of a gene coding for expression of LETS to human chromosome 8. (1978)

Techniques have been developed to analyze the genetics of the large, external, transformation-sensitive (LETS) protein (fibronectin). External membrane proteins of human-mouse somatic cell hybrids with reduced numbers of human but not mouse chromosomes were labeled by lactoperoxidase-catalyzed iodination. Cell surface proteins were identified after sodium dodecyl sulfate/polyacrylamide gel electrophoresis by autoradiography of the dried gel. The LETS protein was identified in parental human cells, and LETS segregated in human-mouse cell hybrids formed from human WI-38 fibroblasts and a mouse L-cell line not expressing LETS. The LETS protein segregated concordantly with the chromosome 8 enzyme marker glutathione reductase (EC 1.6.4.2) and human chromosome 8. These findings demonstrate that a gene, LETS, encoded on chromosome 8, is responsible for the LETS protein expression in humans. Because LETS has been implicated in tumorigenicity and cellular transformation, it is of interest that rearrangement or modifications in the number of chromosome 8 have been associated with certain forms of cancer.
Alterations in the extracellular domain of M13 procoat protein make its membrane insertion dependent on secA and secY (1988)

The products of genes secA and secY (SecA and SecY) are putative components of a bacterial protein export machinery and are required for the export of many periplasmic and membrane proteins. Only a few proteins, among them the M13 procoat protein, insert independently of SecA and SecY. To investigate the reason why the procoat protein inserts independently of sec functions, various hybrid proteins were constructed. By in-frame gene fusions the central procoat region, which translocates across the membrane, was extended in size. Fragments of the ompA gene ranging from 522-294 bp were ligated with the procoat gene. The hybrid proteins were inserted into the membrane and processed normally, but only in the presence of functional SecA and SecY.
Power control for dynamic packet assignment in advanced cellular Internet service (2002)

Wireless broadband networks are expected to employ packet access with high peak-bandwidth demands. This will impose a significant challenge for frequency reuse, especially for the case of ubiquitous services deployed in a wide area. A dynamic packet assignment (DPA) method has been proposed as a key component of the MAC protocol for an OFDM-based advanced cellular Internet service (ACIS) system, which is targeted for applications such as Web browsing, with a peak downlink transmission rate on the order of 1 Mb/s using a wide-area cellular infrastructure. This method is able to allocate radio resources on a packet time scale and reassign them in less than 100 msec, thereby gaining advantages in both statistical multiplexing of packet access and spectrum efficiency of dynamic channel assignment (DCA). One way to achieve very high spectrum efficiency is by using closed-loop SIR-based power control. This paper studies the implementation and performance of various power control methods for DPA in the ACIS environment. It is found that several iterations are required, upon changes of co-channel interference, to update the transmit powers for all active links in order to achieve desirable improvement. However, for a system having many data terminals with short duty cycles, significant overhead may be required for iterative power control. Alternative techniques such as interference suppression, which does not require high iteration overhead, may be attractive options.
Rank-invariant resampling based estimation of false discovery rate for analysis of small sample microarray data (2005)

We found that the SAM's random shuffling and SPLOSH approaches were liberal and the other two theoretical methods were too conservative while our RIR approach provided more accurate FDR estimation than the other approaches.
Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. (2003)

Recent developments in the use of small inhibitory RNA molecules (siRNAs) to inhibit specific protein expression have highlighted the potential use of siRNA as a therapeutic agent. The double-strand break signaling/repair proteins ATM, ATR, and DNA-dependent protein kinase catalytic subunit (DNA-PK(cs)) are attractive targets to confer enhanced radio and chemosensitivity to tumor cells. We have designed and exogenously delivered plasmids encoding siRNAs targeting these critical kinases to human cancer cells to assess the feasibility of this concept as a clinically translatable experimental therapeutic. siRNA led to a approximately 90% reduction in target protein expression. siRNAs targeting ATM and DNA-PK(cs) gave rise to a dose-reduction factor of approximately 1.4 compared with untransfected and control vector-transfected cells at the clinically relevant radiation doses. This was greater than the radiosensitivity achieved using the phosphatidylinositol 3'-kinase inhibitor Wortmannin or DNA-PK(cs) competitive inhibitor LY294002. A similar increased sensitivity to the alkylating agent methyl methanesulfonate (MMS) was also observed for siRNA-mediated ATR silencing. Together, these data provide strong evidence for the potential use of siRNA as a novel radiation/chemotherapy-sensitizing agent.