gebhart/patrepeval huggingface dataset:
Molecular targets for PDE inhibitor-mediated improvement of cardiac dysfunction in the mdx mouse? (2011)

Recent results show that the classic PDE5 inhibitor, Viagra (sildenafil), can ameliorate much of the cardiac pathology resulting from several different forms of cardiac damage. These results have elicited great interest in the use of this drug as a therapeutic agent, particularly for treatment of diastolic cardiac dysfunction. In fact several clinical trials are now enrolling and one published trial shows promising results. Unfortunately, it is not clear how this drug works at a molecular level to improve cardiac function and not even clear what the initial molecular target(s) are for Viagra in any of these studies. Recent data from our group and others strongly suggest that sildenafil, a "classical" PDE5 inhibitor, ameliorates much of the diastolic dysfunction seen in older mdx mice, animals having a disruption in the dystrophin gene. However, our preliminary data suggests that tadalafil does not cause this effect. Moreover, the usual accepted target for sildenafil, PDE5, is not even expressed in adult mouse cardiomyocyes; but an alternate or additional target, PDE1C is highly expressed in this cell type. Since PDE1C, also can be substantially inhibited by sildenafil (but not by tadalafil) we feel that the most likely molecular target for Viagra is a direct effect on PDE1C in the cardiomyocyte itself. There also may be additional effects on PDE5, but probably in another cell type. These topics will be discussed in this talk.
Structure and flexibility of the multiple domain proteins that regulate complement activation (2001)

In this review we summarise more than 10 years of biophysical exploration into the structural biology of the regulators of complement activation (RCA). The five human proteins responsible for regulation of the early events of complement are homologous and are composed largely from building blocks called "complement control protein (CCP) modules". Unlike most multiple domain proteins they do not contain any of the other widely occurring module types. This apparent simplicity of RCA structure, however, is belied by their sophistication of function. In fact, the structures of the individual CCP modules exhibit wide variations on a common theme while the extent and nature of intermodular connections is diverse. Some neighbouring modules within a protein stabilise each other and some co-operate to form specific binding surfaces. The degree of true "modularity" of CCPs is open to debate. The study of RCA proteins clearly illustrates the value of combining complementary structural biology techniques. The results could have implications for folding, evolution, flexibility and structure-function relationships of other molecules in the large, diverse and little understood category of multiple domain proteins.
The proto‐oncogene/translation factor eIF4E: A survey of its expression in breast carcinomas (1995)

The eukaryotic translation initiation factor eIF-4E binds to the cap structure of mRNAs as one component of the eIF-4 translation initiation complex, which mediates the recruitment of mRNA to the ribosomes. Overexpression of eIF-4E can result in oncogenic transformation and uncontrolled growth of mammalian cells, presumably by facilitating the expression of growth-control gene products which are normally translationally repressed. Whereas the mechanism of eIF-4E-mediated transformation is being actively pursued, clinical investigations into the expression of eIF-4E in prevalent human cancers are lacking. We have recently initiated a screen of breast carcinomas by probing with eIF-4E antiserum. Using Western blots, we have analyzed the level of eIF-4E in 38 carcinomas, 7 normal samples and 3 fibroadenomas. We found that eIF-4E was elevated 3- to 10-fold in virtually all the carcinomas we analyzed, but not in fibroadenomas. This analysis was also confirmed by immunohistological staining in situ, showing that overexpression of eIF-4E can be readily identified at the single-cell level. Our results suggest that an elevation of eIF-4E may be an essential component in the development of breast cancer.
Isolation of a Deet-Insensitive Mutant of <I>Drosophila melanogaster</I> (Diptera: Drosophilidae) (2001)

Despite the widespread use of N,N,-diethyl-3-methylbenzamide (deet) in insect repellent products, nothing is known about the molecular basis for the repellency of deet, we initiated a molecular genetics program to elucidate the molecular mechanism of deet repellency in Drosophila melanogaster (Meigen). Deet repellency was apparently due to airborne vapors, as wild type flies were repelled by a deet-treated surface in the absence of physical contact and in the dark. A mutant was isolated using chemical mutagenesis and at choice assay. In a choice assay, mutant flies entered 82 +/- 1% of deet-containing tubes, whereas wild type flies entered only 6 +/- 2% of deet-containing tubes. The mutant was repelled by other repellents, benzaldehyde and citronellal. The mutation was recessive and located on the X chromosome.
Recursive 3-D road and relative ego-state recognition (1992)

The general problem of recognizing both horizontal and vertical road curvature parameters while driving along the road has been solved recursively. A differential geometry representation decoupled for the two curvature components has been selected. Based on the planar solution of E.D. Dickmanns and A. Zapp (1986) and its refinements, a simple spatio-temporal model of the driving process makes it possible to take both spatial and temporal constraints into account effectively. The estimation process determines nine road and vehicle state parameters recursively at 25 Hz (40 ms) using four Intel 80286 and one 386 microprocessors. Results with the test vehicle (VaMoRs), which is a 5-ton van, are given for a hilly country road.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Crystal structure of Taq DNA polymerase in complex with an inhibitory Fab: The Fab is directed against an intermediate in the helix-coil dynamics of the enzyme (1998)

We report the crystal structure of Thermus aquaticus DNA polymerase I in complex with an inhibitory Fab, TP7, directed against the native enzyme. Some of the residues present in a helical conformation in the native enzyme have adopted a gamma turn conformation in the complex. Taken together, structural information that describes alteration of helical structure and solution studies that demonstrate the ability of TP7 to inhibit 100% of the polymerase activity of the enzyme suggest that the change in conformation is probably caused by trapping of an intermediate in the helix-coil dynamics of this helix by the Fab. Antibodies directed against modified helices in proteins have long been anticipated. The present structure provides direct crystallographic evidence. The Fab binds within the DNA binding cleft of the polymerase domain, interacting with several residues that are used by the enzyme in binding the primer:template complex. This result unequivocally corroborates inferences drawn from binding experiments and modeling calculations that the inhibitory activity of this Fab is directly attributable to its interference with DNA binding by the polymerase domain of the enzyme. The combination of interactions made by the Fab residues in both the polymerase and the vestigial editing nuclease domain of the enzyme reveal the structural basis of its preference for binding to DNA polymerases of the Thermus species. The orientation of the structure-specific nuclease domain with respect to the polymerase domain is significantly different from that seen in other structures of this polymerase. This reorientation does not appear to be antibody-induced and implies remarkably high relative mobility between these two domains.
Transforming gene product of Rous sarcoma virus phosphorylates tyrosine (1980)

The protein kinase activity associated with pp60src, the transforming protein of Rous sarcoma virus, was found to phosphorylate tyrosine when assayed in an immunoprecipitate. Despite the fact that a protein kinase with this activity has not been described before, several observations suggest that pp60src also phosphorylates tyrosine in vivo. First, chicken cells transformed by Rous sarcoma virus contain as much as 8-fold more phosphotyrosine than do uninfected cells. Second, phosphotyrosine is present in pp60src itself, at one of the two sites of phosphorylation. Third, phosphotyrosine is present in the 50,000-dalton phosphoprotein that coprecipitates with pp60src extracted from transformed chicken cells. We infer from these observations that pp60src is a novel protein kinase and that the modification of proteins via the phosphorylation of tyrosine is essential to the malignant transformation of cells by Rous sarcoma virus. pp60sarc, the closely related cellular homologue of viral pp60src, is present in all vertebrate cells. This normal cellular protein, obtained from both chicken and human cells, also phosphorylated tyrosine when assayed in an immunoprecipitate. This is additional evidence of the functional similarity of these structurally related proteins and demonstrates that all uninfected vertebrate cells contain at least one protein kinase that phosphorylates tyrosine.
Development of an Ex Vivo Porcine Lung Model for Studying Growth, Virulence, and Signaling of Pseudomonas aeruginosa (2014)

Research into chronic infection by bacterial pathogens, such as Pseudomonas aeruginosa, uses various in vitro and live host models. While these have increased our understanding of pathogen growth, virulence, and evolution, each model has certain limitations. In vitro models cannot recapitulate the complex spatial structure of host organs, while experiments on live hosts are limited in terms of sample size and infection duration for ethical reasons; live mammal models also require specialized facilities which are costly to run. To address this, we have developed an ex vivo pig lung (EVPL) model for quantifying Pseudomonas aeruginosa growth, quorum sensing (QS), virulence factor production, and tissue damage in an environment that mimics a chronically infected cystic fibrosis (CF) lung. In a first test of our model, we show that lasR mutants, which do not respond to 3-oxo-C(12)-homoserine lactone (HSL)-mediated QS, exhibit reduced virulence factor production in EVPL. We also show that lasR mutants grow as well as or better than a corresponding wild-type strain in EVPL. lasR mutants frequently and repeatedly arise during chronic CF lung infection, but the evolutionary forces governing their appearance and spread are not clear. Our data are not consistent with the hypothesis that lasR mutants act as social "cheats" in the lung; rather, our results support the hypothesis that lasR mutants are more adapted to the lung environment. More generally, this model will facilitate improved studies of microbial disease, especially studies of how cells of the same and different species interact in polymicrobial infections in a spatially structured environment.
Amelioration of Neurologic Abnormalities after Enzyme Replacement in Adenosine Deaminase Deficiency (1980)

INHERITED deficiency of the purine salvage enzyme adenosine deaminase (ADA) results in the fatal infantile syndrome of severe combined immunodeficiency.1 2 3 4 The accumulation of the purine substrates of ADA, adenosine and deoxyadenosine and their metabolites, including deoxyadenosine triphosphate (deoxy ATP) and cyclic AMP, appears to provide pathophysiologic mechanisms for lymphoid toxicity.5 6 7 8 9 10 Children with severe combined immunodeficiency due to ADA deficiency are generally indistinguishable clinically from patients with severe combined immunodeficiency of other origins, 2 3 4 but they may have several additional nonimmunologic abnormalities. Bony abnormalities are found in a substantial proportion of ADA-deficient patients, 2 3 4 , 11 and in vitro abnormalities of platelet function have been . . .
EXPLODE: a lightweight, general system for finding serious storage system errors (2006)

Storage systems such as file systems, databases, and RAID systems have a simple, basic contract: you give them data, they do not lose or corrupt it. Often they store the only copy, making its irrevocable loss almost arbitrarily bad. Unfortunately, their code is exceptionally hard to get right, since it must correctly recover from any crash at any program point, no matter how their state was smeared across volatile and persistent memory.This paper describes EXPLODE, a system that makes it easy to systematically check real storage systems for errors. It takes user-written, potentially system-specific checkers and uses them to drive a storage system into tricky corner cases, including crash recovery errors. EXPLODE uses a novel adaptation of ideas from model checking, a comprehensive, heavy-weight formal verification technique, that makes its checking more systematic (and hopefully more effective) than a pure testing approach while being just as lightweight.EXPLODE is effective. It found serious bugs in a broad range of real storage systems (without requiring source code): three version control systems, Berkeley DB, an NFS implementation, ten file systems, a RAID system, and the popular VMware GSX virtual machine. We found bugs in every system we checked, 36 bugs in total, typically with little effort.
Arterial path length measurements required for the pulse wave velocity (2009)

aCardiovascular Aging Research Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, Texas, USA bInstitute for Human Science and Biomedical Engineering, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan Received 7 January, 2009 Revised 13 January, 2009 Accepted 15 January, 2009 Correspondence to Jun Sugawara, PhD, Department of Kinesiology and Health Education, University of Texas at Austin, 1 University Station, D3700 Austin, TX 78712-1204, USA Tel: +1 512 471 8594; fax: +1 512 471 0946; e-mail: [email protected]
An immunomagnetic separation method using superparamagnetic (MACS) beads for large-scale purification of human mammary luminal and myoepithelial cells. (1994)

A comparison has been made between different immunomagnetic techniques for separating normal human mammary epithelial cells based on the exclusive expression of EMA (epithelial membrane antigen) by luminal cells and CALLA (CD10) by myoepithelial cells. When cells labelled with antibodies to these antigens were incubated with Dynabeads, they rosetted myoepithelial but not luminal cells. However, both luminal and myoepithelial cells could be positively separated using the MACS system. Purity was established by analyzing the expression of CALLA and EMA using flow cytometry, and of cell-type specific cytokeratins using indirect immunofluorescence. Dynabead-separated myoepithelial cell populations were of high purity (> 98%) but the beads could not be removed from the cells. Luminal cell populations separated by the MACS method were also highly purified (> 95%), as were myoepithelial cell populations (> 90%). Using this immunomagnetic separation method, up to 10(7) cells of each type could be obtained from individual preparations.
Targeting RAGE Signaling in Inflammatory Disease (2017)

The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA. RAGE can also act as an innate immune sensor of microbial pathogen-associated molecular pattern molecules (PAMPs) including bacterial endotoxin, respiratory viruses, and microbial DNA. RAGE is expressed at low levels under normal physiology, but it is highly upregulated under chronic inflammation because of the accumulation of various RAGE ligands. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammation and progression of diabetic vascular complications, cardiovascular disease (CVD), and cancer progression and metastasis. The clinical relevance of RAGE in inflammatory disease is being demonstrated in emerging clinical trials of novel small-molecule RAGE inhibitors.
Recruitment of neutrophils in the local endotoxin response: association with de novo endothelial expression of endothelial leukocyte adhesion molecule-1. (1991)

Endothelium is central to the cellular infiltration that develops during inflammation, and a prominent feature of its involvement is the expression of adhesion molecules for circulating leukocytes. In the present study, we assessed the kinetics of endothelial adhesion molecule expression during the cutaneous endotoxin response in baboons. Immunostained cryostat sections and hematoxylin and eosin-stained paraffin sections of skin biopsies were examined using set scoring systems to provide semiquantitative data on the changes in endothelial phenotype and induced polymorphonuclear leucocyte (PMN) accumulation. Endothelium in control skin did not express endothelial leukocyte adhesion molecule (ELAM)-1 but did show a relatively weak expression of intercellular adhesion molecule (ICAM)-1. By 2 hours after injection of endotoxin (500 mcg of Escherichia coli-derived lipopolysaccharide), a marked expression of ELAM-1 developed that was associated with concurrent extensive adhesion and extravasation of PMN. The ELAM-1 expression subsequently decreased and was virtually absent by 9 hours. Mean scores for endothelial expression of ICAM-1 changed comparatively little over this time course, and mononuclear cell accumulation was minimal. The response to endotoxin differs from that to tumor necrosis factor injection; the latter causes sustained ELAM-1 expression, and delayed but pronounced increases in ICAM-1, with accompanying mononuclear cell extravasation. Thus, local endotoxin administration provides a model of acute inflammation in which PMN accumulation is associated with striking endothelial expression of ELAM-1. In this model, appreciable elevations in ICAM-1 expression are unnecessary for PMN infiltration.
Lidocaine/Tetracaine Patch (2006)

Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly one-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The March 2006 monograph topics are conivaptan hydrochloride injection, abatacept, sorafenib tosylate, lenalidomide, and tetanus toxoid, reduced diptheria toxoid, and acellular pertussis vaccine absorbed (Tdap). The DUE is on conivaptan.
Specific Absorption Rate as a Poor Indicator of Magnetic Resonance-Related Implant Heating (2005)

Recent publications of the magnetic resonance safety profile of neurostimulators, cardiac pacemakers, and other implanted devices imply that these devices are no longer a contraindication for magnetic resonance imaging. It is very promising that patients who have these implanted devices may in the future no longer be denied an important diagnostic modality. On the other hand, the safety recommendations given in a number of publications included the maximum permissible whole-body specific absorption rate (SAR). This is one factor indicating potential heating, but there are a number of other factors that may have an even higher impact on the potential heating of tissue in the vicinity of leads or implanted devices. Using only the whole-body SAR as a recommendation for a safety profile is potentially dangerous.
Indirubins Inhibit Glycogen Synthase Kinase-3β and CDK5/P25, Two Protein Kinases Involved in Abnormal Tau Phosphorylation in Alzheimer's Disease (2001)

The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment of chronic diseases such as leukemias. The antitumoral properties of indirubin appear to correlate with their antimitotic effects. Indirubins were recently described as potent (IC(50): 50-100 nm) inhibitors of cyclin-dependent kinases (CDKs). We report here that indirubins are also powerful inhibitors (IC(50): 5-50 nm) of an evolutionarily related kinase, glycogen synthase kinase-3beta (GSK-3 beta). Testing of a series of indoles and bis-indoles against GSK-3 beta, CDK1/cyclin B, and CDK5/p25 shows that only indirubins inhibit these kinases. The structure-activity relationship study also suggests that indirubins bind to GSK-3 beta's ATP binding pocket in a way similar to their binding to CDKs, the details of which were recently revealed by crystallographic analysis. GSK-3 beta, along with CDK5, is responsible for most of the abnormal hyperphosphorylation of the microtubule-binding protein tau observed in Alzheimer's disease. Indirubin-3'-monoxime inhibits tau phosphorylation in vitro and in vivo at Alzheimer's disease-specific sites. Indirubins may thus have important implications in the study and treatment of neurodegenerative disorders. Indirubin-3'-monoxime also inhibits the in vivo phosphorylation of DARPP-32 by CDK5 on Thr-75, thereby mimicking one of the effects of dopamine in the striatum. Finally, we show that many, but not all, reported CDK inhibitors are powerful inhibitors of GSK-3 beta. To which extent these GSK-3 beta effects of CDK inhibitors actually contribute to their antimitotic and antitumoral properties remains to be determined. Indirubins constitute the first family of low nanomolar inhibitors of GSK-3 beta to be described.
Conjugates of a Dinuclear Zinc(II) Complex and DNA Oligomers as Novel Sequence-Selective Artificial Ribonucleases (1998)

Even in the presence of a large excess of ZnII ions, sequence-selective RNA hydrolysis is achieved by DNA conjugates involving a dinuclear ZnII complex (shown schematically). This is because the cooperation of two ZnII ions is essential for the RNA scission.
Cordycepin analogs of ppp5'A2‘p5'A2‘p5'A (2-5A) inhibit protein synthesis through activation of the 2-5A-dependent endonuclease. (1985)

Analogs of the triphosphate 2'-5'-linked adenylate trimer (ppp5'A2'p5'A2'p5'A, called 2-5A) which contain 3'-deoxyadenosine (cordycepin) instead of adenosine either in positions one and two, or in all three positions, are 10-100-fold less potent than is parent 2-5A in inhibition of protein synthesis in intact cells, when utilizing calcium co-precipitation techniques to introduce the 5'-triphosphate oligonucleotides into the cells. That the inhibition of protein synthesis was a consequence of activation of the 2-5A-dependent endonuclease by the 3'-deoxyadenosine analogs of 2-5A was demonstrated in obtaining the ribosomal RNA cleavage pattern that is characteristic of endonuclease activation by parent 2-5A. Additional results (i.e. lack of activity by the dimer species ppp5'(3'dA)2'p5'-(3'dA) or the monomer 3'dA) as well as kinetic analysis both in intact cells and in cell-free extracts provided further evidence that the inhibition of protein synthesis observed with these 3'-deoxyadenosine 2-5A analogs was not due to their degradation to the antimetabolite monomer unit 3'-deoxyadenosine.