gebhart/patrepeval huggingface dataset:
Autoproteolysis of herpes simplex virus type 1 protease releases an active catalytic domain found in intermediate capsid particles (1993)

The UL26 gene of herpes simplex virus type 1 (HSV-1) encodes a 635-amino-acid protease that cleaves itself and the HSV-1 assembly protein ICP35cd (F. Liu and B. Roizman, J. Virol. 65:5149-5156, 1991). We previously examined the HSV protease by using an Escherichia coli expression system (I. C. Deckman, M. Hagen, and P. J. McCann III, J. Virol. 66:7362-7367, 1992) and identified two autoproteolytic cleavage sites between residues 247 and 248 and residues 610 and 611 of UL26 (C. L. DiIanni, D. A. Drier, I. C. Deckman, P. J. McCann III, F. Liu, B. Roizman, R. J. Colonno, and M. G. Cordingley, J. Biol. Chem. 268:2048-2051, 1993). In this study, a series of C-terminal truncations of the UL26 open reading frame was tested for cleavage activity in E. coli. Our results delimit the catalytic domain of the protease to the N-terminal 247 amino acids of UL26 corresponding to No, the amino-terminal product of protease autoprocessing. Autoprocessing of the full-length protease was found to be unnecessary for catalysis, since elimination of either or both cleavage sites by site-directed mutagenesis fails to prevent cleavage of ICP35cd or an unaltered protease autoprocessing site. Catalytic activity of the 247-amino-acid protease domain was confirmed in vitro by using a glutathione-S-transferase fusion protein. The fusion protease was induced to high levels of expression, affinity purified, and used to cleave purified ICP35cd in vitro, indicating that no other proteins are required. By using a set of domain-specific antisera, all of the HSV-1 protease cleavage products predicted from studies in E. coli were identified in HSV-1-infected cells. At least two protease autoprocessing products, in addition to fully processed ICP35cd (ICP35ef), were associated with intermediate B capsids in the nucleus of infected cells, suggesting a key role for proteolytic maturation of the protease and ICP35cd in HSV-1 capsid assembly.
Recent development in the topologies for photovoltaic module integrated converters (2006)

The annual world PV cell/module production is growing at almost an exponential rate and has reached 1727 MW In 2005. Building Integrated PV (BIPV) projects are emerging as the strongest part of the PV market and grid Interactive Inverters are a key component in determining the total system cost. Module Integrated Converter (MIC) technology is one approach that may assist In driving down the balance of system costs to secure an Improved total system cost. This paper concentrates on the topology study of the photovoltaic MICs In the power range below 500 W and covers most topologies recently proposed for MIC applications. The MIC topologies are classified into three different arrangements based on the dc link configurations. A systematic discussion is also provided at the end of the paper that focuses on the major advantages and disadvantages of each MIC arrangement. These are considered in detail and will provide a useful framework and point of reference for the next generation MIC designs and applications.
Vaccines for the prevention of human papillomavirus infections. (2006)

Human papillomavirus (HPV) infection is the known cause of almost all cases of cervical cancer. An understanding of the HPV genome has allowed the development of two prophylactic vaccines capable of protecting against both persistent HPV infection and cervical intraepithelial neoplasia (CIN) with 100% efficacy in fully vaccinated women. The vaccines, manufactured by Merck (Gardasil, which was approved by the US FDA in June, 2006) and GlaxoSmithKline (Cervarix, which will be submitted for US FDA approval by the end of 2006), both target HPV types 16 and 18, which together account for 70% of cervical cancer. Merck vaccine also targets HPV 6 and 11, covering =90% of genital warts. These vaccines are highly immunogenic and have an excellent safety profile. HPV vaccines promise to offer an exciting contribution to healthcare and cancer prevention. However, many questions remain concerning who to vaccinate, the duration of protection, cost, public acceptance, and the potential for worldwide distribution.
Meiosis, egg activation, and nuclear envelope breakdown are differentially reliant on Ca2+, whereas germinal vesicle breakdown is Ca2+ independent in the mouse oocyte (1992)

During early development, intracellular Ca2+ mobilization is not only essential for fertilization, but has also been implicated during other meiotic and mitotic events, such as germinal vesicle breakdown (GVBD) and nuclear envelope breakdown (NEBD). In this study, the roles of intracellular and extracellular Ca2+ were examined during meiotic maturation and reinitiation at parthenogenetic activation and during first mitosis in a single species using the same methodologies. Cumulus-free metaphase II mouse oocytes immediately resumed anaphase upon the induction of a large, transient Ca2+ elevation. This resumption of meiosis and associated events, such as cortical granule discharge, were not sensitive to extracellular Ca2+ removal, but were blocked by intracellular Ca2+ chelators. In contrast, meiosis I was dependent on external Ca2+; in its absence, the formation and function of the first meiotic spindle was delayed, the first polar body did not form and an interphase-like state was induced. GVBD was not dependent on external Ca2+ and showed no associated Ca2+ changes. NEBD at first mitosis in fertilized eggs, on the other hand, was frequently, but not always associated with a brief Ca2+ transient and was dependent on Ca2+ mobilization. We conclude that GVBD is Ca2+ independent, but that the dependence of NEBD on Ca2+ suggests regulation by more than one pathway. As cells develop from Ca(2+)-independent germinal vesicle oocytes to internal Ca(2+)-dependent pronuclear eggs, internal Ca2+ pools increase by approximately fourfold.
Treatment of Experimental Brain Injury with Moderate Hypothermia and 21-Aminosteroids (1996)

Studies of experimental traumatic brain injury have found that histologic injury is significantly reduced and behavioral outcome improved in animals treated with moderate hypothermia (32-33 degrees C) or a 21-aminosteroid. Because these treatments are thought to work through different neurochemical mechanisms, their combined use might be expected to be more efficacious than either treatment alone. To test this hypothesis, we studied each treatment separately and in combination in a rodent model of controlled cortical contusion. Treatment with moderate hypothermia (32 degrees C for 4 h), a 21-aminosteroid (U-74389G, Upjohn, 10 mg/kg intravenously, repeated 3 h after the first dose), or both, was initiated 10, 25, or 40 min after injury. The brains were perfused 24 h after injury, and sagittal sections were stained for the 68-kDa "core" neurofilament subunit, a marker of axonal injury. The total number of positively stained axons in the ipsilateral internal capsule were counted under light microscopy. Compared with the control group (injury but no treatment), treatment with each therapy alone or combined, initiated 10 min after injury, caused significant reductions in the number of stained axons (21-aminosteroid alone-35% reduction; hypothermia alone-55% reduction; combination-48% reduction). The number of positively stained axons was significantly reduced in the aminosteroid and combination therapy groups at all three postinjury times (p = 0.01) and in the hypothermia groups treated at 10 or 25 min (p = 0.01) but not at 40 min after injury. We concluded that combination therapy with hypothermia and 21-aminosteroids was no more efficacious than either therapy alone, and that 21-aminosteroid therapy was more efficacious than hypothermia when treatment was initiated 40 min after injury.
The Inference of Regular LISP Programs from Examples (1978)

A class of LISP programs that is analogous to the finite-state automata is defined, and an algorithm is given for constructing such programs from examples of their input-output behavior. It is shown that the algorithm has robust performance for a wide variety of inputs and that it converges to a solution on the basis of minimum input information.
Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: relevance to the therapeutic use of inhibitors of adenosine deaminase (1984)

Deoxyadenosine (AdR) appears to be central to the molecular events mediating immunodeficiency in children born with adenosine deaminase (ADA) deficiency but it is still uncertain whether lymphotoxicity is due to AdR directly inhibiting transmethylation reactions in which S-adenosylmethionine is the methyl group donor, or is due to phosphorylation of AdR to deoxyadenosine triphosphate (dATP) which then inhibits ribonucleotide reductase or is due to other mechanisms. Using AdR and the ADA inhibitor deoxycoformycin (dCF) and assessing cell viability, nucleoside incorporation into RNA and DNA, as well as measuring deoxyribonucleoside triphosphate (dNTP) concentrations and S-adenosylhomocysteine (SAH) hydrolase activity, we have studied various types of human lymphoid cells and demonstrated in them the relative importance of the above two mechanisms of AdR toxicity. Treatment of normal resting peripheral blood lymphocytes in culture with AdR and dCF resulted in impaired viability. Although elevated dATP levels as well as decreased SAH hydrolase activities were both observed, the failure of a known inhibitor of ribonucleotide reductase (hydroxyurea) to produce toxicity, and the inability of deoxycytidine (CdR) to achieve a rescue effect, point to another mechanism, possibly inhibition of trans-methylation or ATP depletion being the more likely causes of toxicity in resting lymphocytes. The same mechanism may well account for the rapid and severe lymphopenia in patients treated with dCF. On the other hand, in cultured lymphoblasts in the exponential phase of growth. AdR and dCF produced marked inhibition of growth and cell death both in a Thy-ALL line and in a c-ALL line, in the absence of significant inhibition of SAH hydrolase, but with a substantial elevation in dATP concentrations and depressed levels of the other dNTP. Minor toxicity occurred in a proliferating B lymphoblast line despite almost complete inactivation of SAH hydrolase. These observations indicate inhibition of ribonucleotide reductase as the more likely mechanism of toxicity in rapidly proliferating lymphocytes. Other T-cells actively synthesizing DNA, such as PHA-stimulated or MLC activated lymphocytes and T-lymphoid colony forming cells, are also likely to be affected by the same mechanism. Indeed in PHA-stimulated lymphocytes, deoxycytidine caused significant although incomplete rescue from toxicity due to dCF and AdR. In patients with ADA deficiency or treated with ADA inhibitors, both mechanisms could be operative. These observations are also relevant to the possible use of dCF and AdR as immunosuppressive agents and for the removal of T-cells or residual Thy-ALL blasts from bone marr
New method for generating deletions and gene replacements in Escherichia coli (1989)

We describe a method for generating gene replacements and deletions in Escherichia coli. The technique is simple and rapid and can be applied to most genes, even those that are essential. What makes this method unique and particularly effective is the use of a temperature-sensitive pSC101 replicon to facilitate the gene replacement. The method proceeds by homologous recombination between a gene on the chromosome and homologous sequences carried on a plasmid temperature sensitive for DNA replication. Thus, after transformation of the plasmid into an appropriate host, it is possible to select for integration of the plasmid into the chromosome at 44 degrees C. Subsequent growth of these cointegrates at 30 degrees C leads to a second recombination event, resulting in their resolution. Depending on where the second recombination event takes place, the chromosome will either have undergone a gene replacement or retain the original copy of the gene. The procedure can also be used to effect the transfer of an allele from a plasmid to the chromosome or to rescue a chromosomal allele onto a plasmid. Since the resolved plasmid can be maintained by selection, this technique can be used to generate deletions of essential genes.
Bioisosterism in Medicinal Chemistry (2012)

This chapter contains sections titled: Introduction Isosterism Bioisosterism Bioisosterism in Lead Optimization Conclusions References
Membrane-permeant Esters of Phosphatidylinositol 3,4,5-Trisphosphate (1998)

Phosphoinositide 3-OH kinases and their products, D-3 phosphorylated phosphoinositides, are increasingly recognized as crucial elements in many signaling cascades. A reliable means to introduce these lipids into intact cells would be of great value for showing the physiological roles of this pathway and for testing the specificity of pharmacological inhibitors of the kinases. We have stereospecifically synthesized di-C<sub>8</sub>-PIP<sub>3</sub>/AM and di-C<sub>12</sub>-PIP<sub>3</sub>/AM, the heptakis(acetoxymethyl) esters of dioctanoyl- and dilauroylphosphatidylinositol 3,4,5-trisphosphate, in 14 steps from <i>myo</i>-inositol. The ability of these uncharged lipophilic derivatives to deliver phosphatidylinositol 3,4,5-trisphosphate across cell membranes was demonstrated on 3T3-L1 adipocytes and T<sub>84</sub> colon carcinoma monolayers. Insulin stimulation of hexose uptake into adipocytes was inhibited by the kinase inhibitor wortmannin and was largely restored by di-C<sub>8</sub>-PIP<sub>3</sub>/AM, which had no effect in the absence of insulin. Thus phosphatidylinositol 3,4,5-trisphosphate or a metabolite was necessary but not sufficient for stimulation of hexose transport. In T<sub>84</sub> epithelial monolayers, di-C<sub>12</sub>-PIP<sub>3</sub>/AM mimicked epidermal growth factor in inhibiting chloride secretion and potassium efflux, suggesting that phosphatidylinositol 3,4,5-trisphosphate was sufficient to modulate these fluxes and mediate epidermal growth factor's action.
Hypoglycemic effects of Aronia melanocarpa fruit juice instreptozotocin-induced diabetic rats (2007)

Aronia melanocarpa fruit juice (AMFJ) is rich in phenolic antioxidants, especially flavonoids from the anthocyanin subclass. The aim of the present study was to investigate the influence of AMFJ on plasma glucose and lipids in diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg). AMFJ was applied by gavage at doses of 10 and 20 ml/kg for 6 weeks to normal and diabetic rats. Streptozotocin caused a significant elevation of plasma glucose by 141% and of plasma triglycerides (TG) by 64% in comparison with normal control rats and induced statistically insignificant elevations of total cholesterol and LDL-cholesterol and a reduction of HDL-cholesterol. Applied to normal rats, AMFJ did not influence plasma glucose and lipid levels. Applied to diabetic rats, AMFJ (10 and 20 ml/kg) significantly reduced plasma glucose by 44% and 42% and TG by 35% and 39%, respectively, to levels that did not significantly differ from those of the normal control rats and counteracted the influence of streptozotocin on total cholesterol, LDL-cholesterol and HDL-cholesterol. In conclusion, AMFJ significantly decreased the streptozotocin-induced abnormalities in blood glucose and TG in diabetic rats and might be useful in prevention and control of diabetes mellitus and diabetes-associated complications.
Relationship of human variable region heavy chain germ-line genes to genes encoding anti-DNA autoantibodies. (1987)

In order to identify the V region genes encoding systemic lupus erythematosus (SLE)-derived anti-DNA autoantibodies, we have determined the nucleotide sequence of heavy chain mRNA from several DNA-binding immunoglobulins secreted by human hybridomas. We used the technique of cDNA primer extension for determining sequences of the VH, D, and JH gene segments of anti-DNA autoantibodies from three different primary hybridoma growths from an SLE patient and one hybridoma from a leprosy patient. Immunoglobulins from two of the SLE hybridomas expressed the same idiotype, Id-16/6, which is also expressed on immunoglobulins in sera of patients with active SLE. Their mRNA sequences showed complete homology to each other in the V, D, and J genes and more than 99% homology to the VH26 germ-line gene sequence, a member of the human VHIII gene family. The VH mRNA sequence of the third SLE hybridoma, 21/28, which was idiotypically unrelated to the other two, was 93% homologous to a different VH germ-line gene sequence, HA2, a member of the human VHI gene family. The fourth anti-DNA-producing hybridoma, 8E10, was derived from a leprosy patient of different ethnic origin than the SLE patient. It was idiotypically related to 21/28 and expressed a VH segment gene identical to that of 21/28. Hybridomas 21/28 and 8E10 shared sequence homology with the VH26 anti-DNA antibodies in the first complementarity-determining region. In addition, 21/28 shared sequence homology with the Id-16/6+ group in the region encoded by the D and J gene segments. Our findings indicate that some SLE autoantibodies are encoded by unmodified or scarcely modified VH germ-line genes that are conserved in the human population and identify two distinct VH germ-line genes that can encode segments of anti-DNA immunoglobulins.
Establishment of a Simple and Practical Procedure Applicable to Therapeutic Angiogenesis (1999)

We propose this procedure as a simple and practical method of therapeutic angiogenesis.
Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. (1999)

Islet amyloid has been recognized as a pathological entity in type 2 diabetes since the turn of the century. It has as its unique component the islet beta-cell peptide islet amyloid polypeptide (IAPP), or amylin, which is cosecreted with insulin. In addition to this unique component, islet amyloid contains other proteins, such as apolipoprotein E and the heparan sulfate proteoglycan perlecan, which are typically observed in other forms of generalized and localized amyloid. Islet amyloid is observed at pathological examination in the vast majority of individuals with type 2 diabetes but is rarely observed in humans without disturbances of glucose metabolism. In contrast to IAPP from rodents, human IAPP has been shown to form amyloid fibrils in vitro. Because all human subjects produce and secrete the amyloidogenic form of IAPP, yet not all develop islet amyloid, some other factor(s) must be involved in islet amyloid formation. One hypothesis is that an alteration in beta-cell function resulting in a change in the production, processing, and/or secretion of IAPP is critical to the initial formation of islet amyloid fibrils in human diabetes. This nidus of amyloid fibrils then allows the progressive accumulation of IAPP-containing fibrils and the eventual replacement of beta-cell mass by amyloid and contributes to the development of hyperglycemia. One factor that may be involved in producing the changes in the beta-cell that result in the initiation of amyloid formation is the consumption of increased dietary fat. Dietary fat is known to alter islet beta-cell peptide production, processing, and secretion, and studies in transgenic mice expressing human IAPP support the operation of this mechanism. Further investigation using this and other models should provide insight into the mechanism(s) involved in islet amyloidogenesis and allow the development of therapeutic agents that inhibit or reverse amyloid fibril formation, with the goal being to preserve beta-cell function and improve glucose control in type 2 diabetes.
Patterning adhesion of mammalian cells with visible light, tris(bipyridyl)ruthenium(II) chloride, and a digital micromirror array (2004)

Abstract Patterns of cellular adhesion were created on a surface using novel photochemistry that is stimulated with visible light. A glass surface coated with polyethylene glycol is nonadhesive to a variety of adherent mammalian cell types. Treatment of that surface with a mixture of tris(bipyridyl)ruthenium(II) chloride, ammonium persulfate, and a tryptophan derivative or tryptophan‐bearing peptide in conjunction with irradiation with visible light (447 nm) made the surface adhesive to several cell types including mouse fibroblasts, human myoblasts, and human lung tumor cells. Immunostaining data suggest that tryptophan‐containing peptides are crosslinked intact to the surface by this chemistry, which enables patterning of peptides containing only naturally occurring amino acids. Microscopic patterns of cellular adhesion were created with this chemistry by projecting microscopic patterns of visible light with a digital micromirror array. Using this method, regions of cellular adhesion were patterned with single‐cell resolution. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 696–703, 2004
The use of heparan sulfate to augment fracture repair in a rat fracture model (2006)

Fracture healing is a complex process regulated by numerous growth and adhesive factors expressed at specific stages during healing. The naturally occurring, cell surface-expressed sugar, heparan sulfate (HS), is known to bind to and potentiate the effects of many classes of growth factors, and as such, may be a potential candidate therapy for enhancing bone repair. This study investigated the local application of bone-derived HS in the repair of rat femoral fractures. After 2 weeks, there was a significant increase in the callus size of rats administered with 5 microg HS compared to the control and 50 microg HS groups, presumably due to increased trabecular bone volume rather than increased cartilage production. In addition, 5 microg HS increased the expression of ALP, Runx2, FGF-1, IGF-II, TGF-beta1, and VEGF. It is hypothesized that these increases resulted from changes in HS-mediated receptor/ligand interactions that increase local growth factor production to augment bone formation. The findings of this study demonstrate the anabolic potential of HS in bone repair by recruiting and enhancing the production of endogenous growth factors at the site of injury.
Characterization of a specific Mycobacterium paratuberculosis recombinant clone expressing 35,000-molecular-weight antigen and reactivity with sera from animals with clinical and subclinical Johne's disease (1997)

Johne's disease is a chronic enteritis of ruminants associated with enormous worldwide economic losses for the dairy cow- and goat-rearing industries. Management limitations and eradication programs for this disease have been hampered by the lack of a simple and specific diagnostic test for the detection of subclinical cases. We used a recombinant clone expressing a 35,000-molecular-weight Mycobacterium paratuberculosis antigen (p35 antigen) from a previously constructed expression library of M. paratuberculosis in Escherichia coli. The DNA fragment encoding the p35 gene hybridized only to DNA from Mycobacterium avium complex, but not to DNAs from other mycobacteria and nonmycobacterial organisms. The seroreactivity of p35 was evaluated by immunoblotting against 57 reference serum samples obtained from infected and uninfected animals. p35 was recognized by sera from 100% of animals with advanced Johne's disease (clinical stage) (12 cattle, 2 goats, and 2 sheep) and by sera from 75% of 20 cattle with early infection (subclinical stage). None of the sera from 15 M. paratuberculosis-free cows, 3 Mycobacterium bovis BCG-infected tuberculous cattle, or 3 cows artificially inoculated with multiple doses of viable M. paratuberculosis reacted with p35. The overall sensitivity, specificity, positive predictive value, and negative predictive value were 86, 100, 100, and 75%, respectively. The accuracy of p35 immunoblotting was superior to those of commercially available diagnostic tests for Johne's disease. These results suggest that the p35 recombinant protein has potential for use in the serodiagnosis of animals with Johne's disease at all stages of infection. The DNA fragment encoding p35 may also serve as a probe for identification of M. avium complex infection.