gebhart/patrepeval huggingface dataset:
Chlamydia Infections and Heart Disease Linked Through Antigenic Mimicry (1999)

Chlamydia infections are epidemiologically linked to human heart disease. A peptide from the murine heart muscle-specific alpha myosin heavy chain that has sequence homology to the 60-kilodalton cysteine-rich outer membrane proteins of Chlamydia pneumoniae, C. psittaci, and C. trachomatis was shown to induce autoimmune inflammatory heart disease in mice. Injection of the homologous Chlamydia peptides into mice also induced perivascular inflammation, fibrotic changes, and blood vessel occlusion in the heart, as well as triggering T and B cell reactivity to the homologous endogenous heart muscle-specific peptide. Chlamydia DNA functioned as an adjuvant in the triggering of peptide-induced inflammatory heart disease. Infection with C. trachomatis led to the production of autoantibodies to heart muscle-specific epitopes. Thus, Chlamydia-mediated heart disease is induced by antigenic mimicry of a heart muscle-specific protein.
Synthesis of N-Methyl-2-trichloroacetylpyrrole-A Key Building Block in Peptides That Bind DNA: Micro-, Semimicro-, and Macro-Scale Organic Lab Experiments (1996)

The search for more efficient anticancer and antiviral agents has included the preparation and testing of a wide variety of molecules that bind DNA. Of these, particular attention has been devoted to the synthesis of analogues of DNA minor-groove binders such as netropsin and distamycin. These compounds have been shown to exhibit biological activity through their strong interactions with the DNA minor groove, and a relationship between their structure and biological activity has emerged (1). The repeating pyrrole unit contained in these compounds can be prepared from N-methylpyrrole via a noncatalyzed Friedel-Crafts acylation. The reaction has been adapted for use in the undergraduate organic chemistry laboratory on three different scales: microscale, semimicroscale, and macroscale.
GLP2-2G-XTEN: A Pharmaceutical Protein with Improved Serum Half-Life and Efficacy in a Rat Crohn’s Disease Model (2012)

GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn's disease model requiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on pharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical pharmacokinetics and dosing indicate that GLP2-2G-XTEN may offer a superior therapeutic benefit for treatment of gastrointestinal diseases including Crohn's disease.
DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia (2009)

Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.
Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains (2013)

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
13 Plant Telomeres (1995)

Plants have served as important experimental organisms in the development of genetics and cytogenetics. This is due in part to historical circumstances, and in part to the agricultural interest in manipulating plant traits. The prominence of plant research also stems from the suitability of plants for cytological observation of the chromosomes and the facility with which transmission genetics can be conducted with plant material. Experiments using plants have played an important part in the study of the chromosome element that is the focus of this monograph. I begin by briefly reviewing McClintock’s studies that helped define the telomere as an essential chromosomal element. I then turn toward more recent studies defining the molecular structure of telomeres in the flowering plants (angiosperms). In large part, this molecular work has a cytogenetic emphasis. Much of the current work in the plant telomere field concerns telomere cytology and genetic mapping. Experimenters are returning to the roots of telomere studies by taking advantage of the genetics and cytology available in plant systems. McCLINTOCK’S EARLY STUDIES ON TELOMERES IN MAIZE The discovery of the unique properties of native chromosome ends was based on observation of the behavior of broken chromosome ends in Drosophila and maize (see Gall, this volume). The paucity of terminal deletions recovered after X-ray-induced breakage of Drosophila chromosomes (for review, see Muller 1938; see also Roberts 1975) led Muller to propose that the “terminal gene” (i.e., telomere) “must have a special function, that of sealing the end of the chromosome” (Muller 1938)...
<title>Thin metal film thermal microsensors</title> (1995)

Design, fabrication, and testing of thermal micro-sensors suitable for miniature and microscopic systems, for application on thin films (free standing or on substrates) as temperature sensors are presented in this paper. The sensors utilize the electrical resistivity temperature dependence of a metal. Using micro-lithography methods, several sets of gold resistors were fabricated in the form of flat 30 to 250 nm thick wires, 7 - 10 micrometers wide, and several cm long in a serpentine shape covering approximately 1.0 mm<SUP>2</SUP>. These sensors have demonstrated better than 0.001 degree(s) C sensitivity. The electrical resistivity and its thermal coefficient of a thin gold metal film were compared with those of bulk material. Temperature measurements on Si wafers were performed in situations corresponding to x-ray lithography exposure conditions suitable for micromachining. The temperature rise and relaxation time of a silicon wafer during x-ray exposure were measured in vacuum and different He gas pressures.
A Sensitive Method for Detecting Variation in Copy Numbers of Duplicated Genes (2003)

Gene duplications are common in the vertebrate genome, and duplicated loci often show a variation in copy number that may have important phenotypic effects. Here we describe a powerful method for quantification of duplicated copies based on pyrosequencing. A reliable quantification was obtained by amplification of the duplication break-point and a corresponding nonduplicated sequence in a competitive PCR assay. A comparison with an independent method for quantification based on the Invader technology revealed an excellent correlation between the two methods. The pyrosequencing-based method was evaluated by analyzing variation in copy number at the duplicated KIT/Dominant white locus in pigs. We were able to distinguish haplotypes at this locus by combining the duplication breakpoint test with a diagnostic test for a functionally important splice mutation in the duplicated gene. An extensive allelic variation, including the presence of a new allele carrying a single KIT copy expected to encode a truncated KIT receptor, was revealed when analyzing white pigs from commercial lines.
Inhibition of Apoptosis Blocks Human Motor Neuron Cell Death in a Stem Cell Model of Spinal Muscular Atrophy (2012)

Spinal muscular atrophy (SMA) is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC) lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients.
Fourier slice photography (2005)

This paper contributes to the theory of photograph formation from light fields. The main result is a theorem that, in the Fourier domain, a photograph formed by a full lens aperture is a 2D slice in the 4D light field. Photographs focused at different depths correspond to slices at different trajectories in the 4D space. The paper demonstrates the utility of this theorem in two different ways. First, the theorem is used to analyze the performance of digital refocusing, where one computes photographs focused at different depths from a single light field. The analysis shows in closed form that the sharpness of refocused photographs increases linearly with directional resolution. Second, the theorem yields a Fourier-domain algorithm for digital refocusing, where we extract the appropriate 2D slice of the light field's Fourier transform, and perform an inverse 2D Fourier transform. This method is faster than previous approaches.
Atomic control of substrate termination and heteroepitaxial growth of SrTiO3/LaAlO3 films (2016)

The roles of substrate termination in the growth behaviors of SrTiO3 (STO) films were investigated. With heat treatment and an atomic layer deposition technique, LaAlO3 (LAO) substrates with two kinds of terminations, i.e., LaO- and AlO2-terminated ones, could be prepared. On top of them, STO films were grown by using laser molecular beam epitaxy. In the case of the STO/LaO-LAO film, a transition from layer-by-layer growth to island growth was observed after growth of about 10 monolayers (ML). On the other hand, the STO/AlO2-LAO him could be grown in a layer-by-layer mode with a flat surface up to 40 ML. We suggest that defects induced by charge compensatoin influence the strain states and the physical properties of oxide heterostructures significantly.
Estrogens and the Vascular Endothelium (2002)

Estrogens exert important regulatory functions on vessel wall components, which may contribute to the increased prevalence and severity of certain chronic inflammatory and autoimmune diseases in females and the lower cardiovascular risk observed in premenopausal women. Endothelial cells have been recently identified as targets for estrogens, and estrogen receptors have been demonstrated in endothelial cells from various vascular beds. This review focuses on the regulatory function of estrogens in endothelial cell responses relevant to vessel inflammation, injury, and repair; estrogen effects on nitric oxide production and release; estrogen modulation of endothelial cell adhesion molecule expression; and estrogen regulation of angiogenesis. The mechanisms through which estrogen regulates endothelial cell functions are complex and involve both genomic and nongenomic mechanisms.
Dynamic Regulation of Platelet-Derived Growth Factor Receptor α Expression in Alveolar Fibroblasts during Realveolarization (2012)

Although the importance of platelet-derived growth factor receptor (PDGFR)-α signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-α-expressing cells induce α smooth muscle actin (α-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-γ activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-γ signaling in differentiation of myofibroblasts from PDGFR-α-positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-γ signaling was activated by administration of rosiglitazone. Changes in α-SMA and PDGFR-α protein expression were assessed in PDGFR-α-green fluorescent protein (GFP) reporter mice using immunohistochemistry, flow cytometry, and real-time PCR. Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of PDGFR-α-GFP changed dynamically during alveolar regeneration and that α-SMA expression was induced in a subset of PDGFR-α-GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of α-SMA in PDGFR-α-positive fibroblasts and formation of new septae. Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy, and results demonstrated that inhibition of FGFR2 signaling and increase in PPAR-γ signaling altered the expression of Shh, FGF, Wnt, and Bmp4, genes that are also important for epithelial-mesenchymal crosstalk during early lung development. Our data demonstrate for the first time that a comparable epithelial-mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation.
Classifying Cancers Based on T-cell Infiltration and PD-L1 (2015)

Cancer immunotherapy may become a major treatment backbone in many cancers over the next decade. There are numerous immune cell types found in cancers and many components of an immune reaction to cancer. Thus, the tumor has many strategies to evade an immune response. It has been proposed that four different types of tumor microenvironment exist based on the presence or absence of tumor-infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression. We review this stratification and the latest in a series of results that shed light on new approaches for rationally designing ideal combination cancer therapies based on tumor immunology.
Age‐Related Decrease in Cold‐Activated Brown Adipose Tissue and Accumulation of Body Fat in Healthy Humans (2011)

Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 °C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.
Oxidant stress reduces insulin responsiveness in 3T3-L1 adipocytes (1997)

Increased oxidant stress has been suggested to occur in diabetes and to contribute to the development of late diabetic complications. Whether oxidant stress plays a role in the development or progression of insulin resistance is not known. In this study we hypothesized that exposing 3T3-L1 adipocytes to prolonged micromolar concentrations of H2O2 would reduce their acute metabolic responses to insulin stimulation. 3T3-L1 adipocytes exposed to 25 mU/ml glucose oxidase (GO) for 18 h exhibited a threefold increase in basal 2-deoxyglucose (2-DG) uptake activity. However, net increase in 2-DG uptake activity after acute insulin (100 nM) stimulation was 355 +/- 56 pmol.mg protein-1.min-1 in control vs. 198 +/- 41 pmol.mg protein-1.min-1 in GO-pretreated cells (P < 0.05). Basal lipogenesis activity was significantly enhanced by GO, but acute insulin stimulation resulted in significantly reduced lipogenesis activity (29 +/- 4 vs. 11 +/- 1 nmol glucose/well for control and 50 mU/ml GO, respectively, P = 0.001). Glycogen synthase alpha activity was reduced by GO (78 +/- 1 vs. 43 +/- 2 pmol UDP-glucose.mg protein-1.min-1, P = 0.03), whereas insulin stimulation of glycogen synthase was reduced, exhibiting a right shift in the insulin dose-response curve. These effects of GO were associated with increased GLUT-1 and reduced GLUT-4 protein and mRNA content. In conclusion, our data suggest that oxidant stress alters glucose transporters expression and insulin-stimulated metabolism in 3T3-L1 adipocytes.
Structural basis for the binding of an anti-cytochrome c antibody to its antigen: crystal structures of FabE8-cytochrome c complex to 1.8 å resolution and FabE8 to 2.26 å resolution (1998)

A complete understanding of antibody-antigen association and specificity requires the stereochemical description of both antigen and antibody before and upon complex formation. The structural mechanism involved in the binding of the IgG1 monoclonal antibody E8 to its highly charged protein antigen horse cytochrome c (cyt c) is revealed by crystallographic structures of the antigen-binding fragment (Fab) of E8 bound to cyt c (FabE8-cytc), determined to 1.8 A resolution, and of uncomplexed Fab E8 (FabE8), determined to 2.26 A resolution. E8 antibody binds to three major discontiguous segments (33 to 39; 56 to 66; 96 to 104), and two minor sites on cyt c opposite to the exposed haem edge. Crystallographic definition of the E8 epitope complements and extends biochemical mapping and two-dimensional nuclear magnetic resonance with hydrogen-deuterium exchange studies. These combined results demonstrate that antibody-induced stabilization of secondary structural elements within the antigen can propagate locally to adjacent residues outside the epitope. Pre-existing shape complementarity at the FabE8-cytc interface is enhanced by 48 bound water molecules, and by local movements of up to 4.2 A for E8 antibody and 8.9 A for cyt c. Glu62, Asn103 and the C-terminal Glu104 of cyt c adjust to fit the pre-formed VL "hill" and VH "valley" shape of the grooved E8 paratope. All six E8 complementarity determining regions (CDRs) contact the antigen, with CDR L1 forming 46% of the total atomic contacts, and CDRs L1 (29%) and H3 (20%) contributing the highest percentage of the total surface area of E8 buried by cyt c (550 A2). The E8 antibody covers 534 A2 of the cyt c surface. The formation of five ion pairs between E8 and flexible cyt c residues Lys60, Glu62 and Glu104 suggests the importance of mobile regions and electrostatic interactions in providing the exquisite specificity needed for recognition of this extremely conserved protein antigen. The highly homologous VL domains of E8 and anti-lysozyme antibody D1. 3 achieve their distinct antigen-binding specificities by expanding the impact of their limited sequence differences through the recruitment of different sets of conserved residues and distinctly different CDR L3 conformations.
Analysis of Prolapse in Cardiovascular Stents: A Constitutive Equation for Vascular Tissue and Finite-Element Modelling (2003)

The effectiveness of a cardiovascular stent depends on many factors, such as its ability to sustain the compression applied by the vessel wall, minimal longitudinal contraction when it is expanded, and its ability to flex when navigating tortuous blood vessels. The long-term reaction of the tissue to the stent is also device dependant; in particular some designs provoke in-stent restenosis (i.e., regrowth of the occlusion around the stent). The mechanism of restenosis is thought to involve injury or damage to the vessel wall due to the high stresses generated around the stent when it expands. Because of this, the deflection of the tissue between the struts of the stent (called prolapse or "draping") has been used as a measure of the potential of a stent to cause restenosis. In this paper, uniaxial and biaxial experiments on human femoral artery and porcine aortic vascular tissue are used to develop a hyperelastic constitive model of vascular tissue suitable for implementation in finite-element analysis. To analyze prolapse, four stent designs (BeStent 2, Medtronic AVE; NIROYAL, Boston Scientific; VELOCITY, Cordis; TETRA, Guidant) were expanded in vitro to determine their repeating-unit dimensions. This geometric data was used to generate a finite element model of the vascular tissue supported within a repeating-unit of the stent. Under a pressure of 450 mm Hg (representing the radial compression of the vessel wall), maximum radial deflection of 0.253 mm, 0.279 mm, 0.348 mm and 0.48 mm were calculated for each of the four stents. Stresses in the vascular wall were highest for the VELOCITY stent. The method is proposed as a way to compare stents relative to their potential for restenosis and as a basis for a biomechanical design of a stent repeating-unit that would minimize restenosis.
Control of intra-ocular inflammation associated with cataract surgery (2001)

Postoperative ocular inflammation following cataract surgery is related to the risk of complications like corneal edema, intraocular pressure spikes, cystoid macular edema, and posterior capsule opacification. The degree of postoperative inflammation following cataract surgery is linked to several surgery-dependent factors such as surgical technique, intraocular lens type, and also patient-dependent factors such as history of inflammatory disease and degree of iris pigmentation. During the past decade, major advances have occurred in cataract surgery techniques, equipment, and pharmacologic strategies that decrease the degree of postoperative inflammation following cataract surgery and reduce patients' risk for inflammation-related complications. This article reviews the most recent literature regarding the control of cataract surgery-induced intra-ocular inflammation.