gebhart/patrepeval huggingface dataset:
Cross-linking of Wild-type and Mutant α2-Antiplasmins to Fibrin by Activated Factor XIII and by a Tissue Transglutaminase (2000)

Human alpha(2)-antiplasmin (alpha(2)AP), the main inhibitor of plasmin-mediated fibrinolysis, is a substrate for plasma transglutaminase, also termed activated factor XIII (FXIIIa). Of 452 amino acids in alpha(2)AP, only Gln(2) is believed to be a fibrin-cross-linking (or FXIIIa-reactive) site. Kinetic efficiencies (k(cat)/K(m)((app))) of FXIIIa and the guinea pig liver tissue transglutaminase (tTG) and reactivities of Gln substrate sites were compared for recombinant wild-type alpha(2)AP (WT-alpha(2)AP) and Q2A mutant alpha(2)AP (Q2A-alpha(2)AP). [(14)C]Methylamine incorporation showed the k(cat)/K(m)((app)) of FXIIIa to be 3-fold greater than that of tTG for WT-alpha(2)AP. With FXIIIa or tTG catalysis, [(14)C]methylamine was incorporated into Q2A-alpha(2)AP, indicating that WT-alpha(2)AP has more than one Gln cross-linking site. To identify transglutaminase-reactive sites in WT-alpha(2)AP or Q2A-alpha(2)AP, each was labeled with 5-(biotinamido)pentylamine by FXIIIa or tTG catalysis. After each labeled alpha(2)AP was digested by trypsin, sequence and mass analyses of each labeled peptide showed that 4 of 35 Gln residues were labeled with the following reactivities: Gln(2) > Gln(21) > Gln(419) > Gln(447). Q(2)A-alpha(2)AP was also labeled at Gln(21) > Gln(419) > Gln(447), but became cross-linked to fibrin by FXIIIa or tTG at approximately one-tenth the rate for WT-alpha(2)AP. These results show that alpha(2)AP is a better substrate for FXIIIa than for this particular tTG, but that either enzyme involves the same Gln substrate sites in alpha(2)AP and yields the same order of reactivities.
GPS-less Low Cost Outdoor Localization For Very Small Devices (2000)

Abstract — Instrumenting the physical world through large networks of wireless sensor nodes, particularly for ap-plications like marine biology, requires that these nodes be very small, light, un-tethered and unobtrusive, imposing sub-stantial restrictions on the amount of additional hardware that can be placed at each node. Practical considerations such as the small size, form factor, cost and power con-straints of nodes preclude the use of GPS(Global Position-ing System) for all nodes in these networks. The problem of localization, i.e., determining where a given node is physi-cally located in a network is a challenging one, and yet ex-tremely crucial for many applications of very large device networks. It needs to be solved in the absence of GPS on all the nodes in outdoor environments. In this paper, we propose a simple connectivity-metric based method for localization in outdoor environments that makes use of the inherent radio-frequency(RF) communications capabilities of these devices. A fixed number of reference points in the network transmit periodic beacon signals. Nodes use a simple connectivity metric to infer proximity to a given subset of these reference points and then localize themselves to the centroid of the lat-ter. The accuracy of localization is then dependent on the separation distance between two adjacent reference points and the transmission range of these reference points. Initial experimental results show that the accuracy for 90 % of our data points is within one-third of the separation distance. Keywords—localization, radio, wireless, GPS-less, con-nectivity, sensor networks.
Synthesis and optical properties of colloidal germanium nanocrystals (2001)

Highly crystalline germanium (Ge) nanocrystals in the size range 2--10 nm were grown in inverse micelles and purified and size separated by high-pressure liquid chromatography with on-line optical and electrical diagnostics. The nanocrystals retain the diamond structure of bulk Ge down to at least 2.0 nm (containing about 150 Ge atoms). One of the objectives of the work was to demonstrate visible light emission from these nanocrystals, and, as it turned out, this dictated emphasis on small (5 nm) sizes. The background- and impurity-free extinction and photoluminescence (PL) spectra of 2 and 4 nm nanocrystals revealed rich structure which could be interpreted in terms of the band structure of Ge shifted to higher energies by quantum confinement. The sifts ranged from \ensuremath{\sim}0.1 eV to over 1 eV for the various transitions. PL in the range 350--700 nm was observed from nanocrystals 2--5 nm in size. The 2.0-nm nanocrystals yielded the most intense PL (at 420 nm) which is believed to be intrinsic and attributed to direct recombination at \ensuremath{\Gamma}. Excitation at high energy (250 nm) populates most of the conduction bands resulting in competing recombination channels and the observed broad PL spectra.
Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. (1996)

Degradable matrices containing expression plasmid DNA [gene-activated matrices (GAMs)] were implanted into segmental gaps created in the adult rat femur. Implantation of GAMs containing beta-galactosidase or luciferase plasmids led to DNA uptake and functional enzyme expression by repair cells (granulation tissue) growing into the gap. Implantation of a GAM containing either a bone morphogenetic protein-4 plasmid or a plasmid coding for a fragment of parathyroid hormone (amino acids 1-34) resulted in a biological response of new bone filling the gap. Finally, implantation of a two-plasmid GAM encoding bone morphogenetic protein-4 and the parathyroid hormone fragment, which act synergistically in vitro, caused new bone to form faster than with either factor alone. These studies demonstrate for the first time that repair cells (fibroblasts) in bone can be genetically manipulated in vivo. While serving as a useful tool to study the biology of repair fibroblasts and the wound healing response, the GAM technology may also have wide therapeutic utility.
Targeting MYC dependence in cancer by inhibiting BET bromodomains (2011)

The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G(1) arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.
Synthesis of Novel 3‘-C-Methylene Thymidine and 5-Methyluridine/Cytidine H-Phosphonates and Phosphonamidites for New Backbone Modification of Oligonucleotides (2001)

Novel 5'-O-DMT- and MMT-protected 3'-C-methylene-modified thymidine, 5-methyluridine, and 5-methylcytidine H-phosphonates 1-7 with O-methyl, fluoro, hydrogen, and O-(2-methoxyethyl) substituents at the 2'-position have been synthesized by a new effective strategy from the corresponding key intermediates 3'-C-iodomethyl nucleosides and intermediate BTSP, prepared in situ through the Arbuzov reaction. The modified reaction conditions for the Arbuzov reaction prevented the loss of DMT- and MMT-protecting groups, and directly provided the desired 5'-O-DMT- and/or MMT-protected 3'-C-methylene-modified H-phosphonates 1-6 although some of them were also prepared through the manipulation of protecting groups after the P-C bond formation. The modified Arbuzov reaction of 3'-C-iodomethyl-5-methylcytidine 53, prepared from its 5-methyluridine derivative 42, with BTSP provided the 5-methylcytidine H-phosphonate 54, which was further transferred to the corresponding 4-N-(N-methylpyrrolidin-2-ylidene)-protected H-phosphonate monomer 7. 5'-O-MMT-protected 3'-C-methylene-modified H-phosphonates 5, 3, and 7 were converted to the corresponding cyanoethyl H-phosphonates 50, 51, and 56 using DCC as a coupling reagent. One-pot three-step reactions of 50, 51, and 56 provided the desired 3'-C-methylene-modified phosphonamidite monomers 8-10. Some of these new 3'-methylene-modified monomers 1-10 have been successfully utilized for the synthesis of 3'-methylene-modified oligonucleotides, which have shown superior antisense properties including nuclease resistance and binding affinity to the target RNA.
A3 adenosine receptor as a target for cancer therapy (2002)

Targeting the A3 adenosine receptor (A3AR) by adenosine or a synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) results in a differential effect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor cell types such as melanoma, colon or prostate carcinoma and lymphoma. This effect is specific and is exerted on tumor cells only. Moreover, exposure of peripheral blood mononuclear cells to adenosine or the agonists leads to the induction of granulocyte colony stimulating factor (G-CSF) production. When given orally to mice, the agonists suppress the growth of melanoma, colon and prostate carcinoma in these animals, while inducing a myeloprotective effect via the induction of G-CSF production. The de-regulation of the Wnt signaling pathway was found to be involved in the anticancer effect. Receptor activation induces inhibition of adenylyl cyclase with a subsequent decrease in the level of protein kinase A and protein kinase B/Akt leading to activation of glycogen synthase kinase-3beta, a key element in the Wnt pathway. The oral bioavailability of the synthetic A3AR agonists, and their induced systemic anticancer and myeloprotective effect, renders them potentially useful in three different modes of treatment: as a stand-alone anticancer treatment, in combination with chemotherapy to enhance its therapeutic index and myelprotection. It is evident that use of the A3AR agonist for increasing the therapeutic index of chemotherapy may also invariably give rise to myeloprotection and vice versa. The A3AR agonists are thus a promising new class of agents for cancer therapy.
Improved Emulsifying and Foaming of Whey Proteins after Enzymic Fat Hydrolysis (1997)

ABSTRACT In an effort to improve emulsifying and foaming of sweet whey and whey protein concentrate, we studied the hydrolysis of the residual fat in these preparations with a sn 1,3 specific lipase. This enzymatic lipolysis would convert almost all triglycerides into mono‐ and diglycerides which have strong surface‐active properties. Therefore, the emulsifying and foaming capacities of such modified whey products should be increased in comparison with native products, as shown by results presented at both neutral pH and those similar to a salad dressing emulsion. It was also demonstrated that emulsions and foams formed with lipasetreated whey preparations were more shelf‐stable.
Microbial genome sequencing (2000)

Complete genome sequences of 30 microbial species have been determined during the past five years, and work in progress indicates that the complete sequences of more than 100 further microbial species will be available in the next two to four years. These results have revealed a tremendous amount of information on the physiology and evolution of microbial species, and should provide novel approaches to the diagnosis and treatment of infectious disease.
Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108 (2006)

The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1z/Sle1bz, and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1z/Sle1bz impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1bz, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.
The tertiary structure and domain organization of coagulation factor VIII (2007)

Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.
Protamine–histone replacement and DNA replication in the male mouse pronucleus (1990)

The protamine to histone replacement in fertilized mouse eggs was studied by using antibodies to these proteins. Its course was followed with respect to DNA replication by autoradiography of 3H-thymidine-labeled fertilized eggs. It was found that protamines were replaced by histones before the onset of DNA replication.
Total Synthesis of Epohelmin B and Its Analogues (2007)

A concise synthesis of the pyrrolizidine alkaloid epohelmin B (1) and a series of analogues is described. The key steps en route to this lanosterol synthase (oxidosqualene cyclase) inhibitor comprise a highly practical "azonia-Cope rearrangement", which sets the chiral amine center with excellent optical purity, a ring-closing metathesis (RCM) reaction catalyzed by a readily prepared and now also commercially available ruthenium-indenylidene complex, a manganese-catalyzed epoxidation of the resulting eight-membered cycloalkene derivative, and a nosyl-deprotection/transannular-epoxide-opening cascade to forge the pyrrolizidine core. Digression from the route leading to the natural product in the final stages allowed for the preparation of several "epohelmin-like" compounds with modified side chains, which is necessary for investigations into a possible functional relationship with other known lanosterol synthase inhibitors.
Using Deuterium in Drug Discovery: Leaving the Label in the Drug (2013)

Deuterium, the stable isotope of hydrogen, is known to medicinal chemists for its utility in mechanistic, spectroscopic, and tracer studies. In fact, well-known applications utilizing deuterium exist within every subdiscipline in pharmaceutical discovery and development. Recent emphasis on incorporation of deuterium into the active pharmaceutical ingredient has come about as a result of inquiries into the potential for substantial benefits of the deuterium kinetic isotope effect on the safety and disposition of the drug substance. This Perspective traces the author's experience in reviving and expanding this potential utility, first suggested many decades prior by the discoverer of this, the simplest of all isotopes.
An adenosine-to-inosine tRNA-editing enzyme that can perform C-to-U deamination of DNA (2007)

Adenosine-to-inosine editing in the anticodon of tRNAs is essential for viability. Enzymes mediating tRNA adenosine deamination in bacteria and yeast contain cytidine deaminase-conserved motifs, suggesting an evolutionary link between the two reactions. In trypanosomatids, tRNAs undergo both cytidine-to-uridine and adenosine-to-inosine editing, but the relationship between the two reactions is unclear. Here we show that down-regulation of the Trypanosoma brucei tRNA-editing enzyme by RNAi leads to a reduction in both C-to-U and A-to-I editing of tRNA in vivo. Surprisingly, in vitro, this enzyme can mediate A-to-I editing of tRNA and C-to-U deamination of ssDNA but not both in either substrate. The ability to use both DNA and RNA provides a model for a multispecificity editing enzyme. Notably, the ability of a single enzyme to perform two different deamination reactions also suggests that this enzyme still maintains specificities that would have been found in the ancestor deaminase, providing a first line of evidence for the evolution of editing deaminases.
Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp (2015)

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.
Factors Influencing Luxury Uptake of Phosphorus by Microalgae in Waste Stabilization Ponds (2008)

Phosphorus removal in waste stabilization ponds (WSP) is highly variable, but the reasons for this are not well understood. Luxury uptake of phosphorus by microalgae has been studied in natural systems such as lakes but not under the conditions found in WSP. This work reports on the effects of phosphate concentration, light intensity, and temperature on luxury uptake of phosphorus by WSP microalgae in continuous culture bioreactors. Increasing temperature had a statistically significant "positive effect" on intracellular acid-insoluble polyphosphate concentration. It is likely that elevated temperature increased the rate of polyphosphate accumulation, but because the biomass was not starved of phosphate, the stored acid-insoluble polyphosphate was not utilized. Increasing light intensity had no effect on acid-insoluble polyphosphate but had a "negative effect" on the acid-soluble polyphosphate. A possible explanation for this is that the faster growth rate at high light intensity results in this form of polyphosphate being utilized by the cells for synthesis of cellular constituents at a rate that exceeds replenishment. The variability in the phosphorus content of the microalgal biomass shows that with this new understanding ofthe luxury uptake mechanism there is the potential to optimize WSP for biological phosphorus removal.
CMOS in camera (1994)

The author explains how a device small enough to fit inside a car&apos;s rear-view mirror can be programmed to see. The device is a CMOS based image sensor developed by VLSI Vision Ltd., Edinburgh. The sensor overcomes the previous problem of placing all pixel outputs through a single charge amplifier by using a separate charge-sense amplifier at the head of each column of pixels. The author describes how the sensor operates. The incorporation of this sensor into a programmable machine-vision system called the imputer is discussed.
Envelope Glycoprotein Binding to the Integrin α 4 β 7 Is Not a General Property of Most HIV-1 Strains (2014)

Certain HIV-1 gp120 envelope glycoproteins have been shown to bind the gut-homing receptor α4β7, and it has been suggested that this binding facilitates mucosal transmission and virus replication in the gut mucosa. Additional evidence has generated the hypothesis that antibodies that bind near the putative α4β7 binding motif in the V2 loop of gp120, possibly disrupting gp120-α4β7 binding, may be important for HIV-1 vaccines. Our evidence indicates that infectious HIV-1 virions and many gp120s lack detectable α4β7 binding activity, suggesting that this homing receptor may play a limited role in direct HIV-1 infection of cells.
Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331: a water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. (1997)

ZD9331 is a drug that was developed from a potent class of water-soluble, C7-methyl-substituted, quinazoline-based inhibitors of thymidylate synthase (TS) that are transported into cells via a saturable, carrier-mediated system (reduced folate carrier, or RFC) but are not substrates for folylpolyglutamate synthetase. ZD9331 is the gamma-tetrazole analogue of 2-desamino-2, 7-dimethyl-N10-propargyl-2'fluoro-5,8-dideaza folate (ZM214888), with a TS Ki of approximately 0.4 nM. ZD9331 exhibits potent growth inhibitory and cytotoxic activity; e.g., IC50 for the inhibition of human W1L2 lymphoblastoid cell line was 7 nM. The addition of thymidine to the culture medium increased the IC50 in W1L2 cells >10, 000-fold, demonstrating the high specificity of the drug for TS. ZD9331 is transported into cells predominantly via the RFC. Accordingly, it competes with methotrexate (MTX) and folinic acid for cellular uptake and has reduced activity against two cell lines with low expression of the RFC (L1210:1565 and CEM/MTX). In addition, a cell line with acquired resistance to ZD9331 displays reduced uptake of both ZD9331 and MTX. A mouse cell line (L1210:RD1694), with acquired resistance to ZD1694 due to reduced folylpolyglutamate synthetase activity, was not significantly cross-resistant to ZD9331. The flux through TS, as measured by 3H release from 5-[3H]deoxyuridine, was rapidly inhibited when cells were incubated with ZD9331. However, because ZD9331 cannot form polyglutamates, TS activity recovered rapidly once cells were placed in drug-free medium. The minimum curative dose of ZD9331 in the i.m. L5178Y TK-/- tumor model was approximately 3 mg/kg when given by 24-h continuous infusion, and it was 25-50 mg/kg when given by a single i.p. or i.v. injection. ZD9331 had antitumor activity against the L5178Y TK+/- tumor when administered by 7-day continuous infusion; growth delays of more than 5 days (and some cures) were seen at doses of 25-50 mg/kg/day. At higher doses, significant weight loss (gastrointestinal toxicity) and myelosuppression (neutropenia and thrombocytopenia) were observed, suggesting that these may be dose-limiting toxicities in the Phase I clinical studies.
Direct transport of progesterone from vagina to uterus (2000)

Ratios of endometrial to serum progesterone concentrations were higher after vaginal administration of progesterone than after IM injections. Our findings in endometrial tissue specimens from hysterectomies excluded the possibility of contamination by progesterone that remained in the vagina.