gebhart/patrepeval huggingface dataset:
Endotoxin tolerance protects against local hepatic ischemia/reperfusion injury in the rat (2000)

Liver surgery and liver transplantation as well as circulatory shock are often associated with hepatic ischemia/reperfusion (I/R) injury. Recent evidence suggests that TNF-alpha plays a central role in I/R injury and, therefore, down-regulation of TNF-alpha seems to be a promising way to protect against the deleterious consequences of I/R. Endotoxin tolerance represents a state of unresponsiveness to endotoxin and is associated with diminished TNF-alpha production. Thus, the effect of endotoxin tolerance on hepatic I/R injury of the liver was investigated in a rat model. I/R injury was induced by temporary ischemia of the left lateral liver lobe for 90 min followed by a 3 h observation period of reperfusion. I/R injury resulted in functional hepatic disorder characterized by a decrease both in bile flow and bile acid concentration and 50% mortality. This was prevented by induction of endotoxin tolerance. Hepatic TNF-alpha mRNA expression after I/R of the liver was determined by RT-PCR. In untreated rats, TNF-alpha mRNA was induced in the liver 60 min after reperfusion and further increased until 3 h after reperfusion. In contrast, in endotoxin-tolerant rats, no increases in TNF-alpha mRNA expression were detected. This suggests that induction of endotoxin tolerance protects against hepatic I/R injury possibly via down-regulation of intra-organ TNF-alpha expression.
Combining Edges and Points for Interactive Anti-Aliased Rendering (2002)

This paper presents a new rendering and display paradigm that uses both discontinuities (edges) and sparsely sampled shading (points) to interactively generate anti-aliased images of complex scenes. Geometric and shadow discontinuities in the image are found at interactive rates using a novel data structure, the Normal–Position Interval tree, and algorithms based on interval arithmetic. After projecting discontinuities onto the image plane, shading information is interpolated from nearby point samples while never interpolating across a discontinuity edge. We introduce a new compact representation of the discontinuities and point samples called the edge-andpoint image. An efficient interpolation algorithm uses this image to generate anti-aliased output images at interactive rates without using supersampling. Our rendering technique is extensible, permitting the use of arbitrary shaders to collect radiance samples. Our software implementation supports interactive navigation and object manipulation in scenes that include complex lighting effects (such as global illumination) and geometrically complex objects. We show that highquality anti-aliased images of these scenes can be rendered at several frames per second on typical desktop machines. 1
Polymerase Chain Reaction Species Diagnostic Assay for Anopheles quadrimaculatus Cryptic Species (Diptera: Culicidae) Based on Ribosomal DNA ITS2 Sequences (1996)

Species-specific differences in the nucleotide sequences of the 2nd internal transcribed spacer (ITS2) of nuclear ribosomal DNA (rDNA) were used to develop a diagnostic assay based on the polymerase chain reaction (PCR) that can distinguish 4 of the 5 cryptic sibling species in the common malaria mosquito, Anopheles quadrimaculatus Say, complex. The assay requires only a small amount of tissue from an individual mosquito and a mixture of 5 PCR primers. The plus strand universal primer is derived from a sequence in the 5.8S coding region that is identical in all members of the complex. The 4 minus strand primers were selected from species-unique sequences within the ITS2 region. PCR amplification produces a different sized fragment for each of the 4 species which can be visualized readily under ultraviolet light after electrophoresis through an ethidium bromide-containing agarose gel. The assay has been developed and tested only with An. quadrimaculatus complex specimens from Florida populations.
PhysioNet: a research resource for studies of complex physiologic and biomedical signals (2002)

PhysioNet (http://www.physionet.org/) is a web-based resource supplying well-characterized physiologic signals and related open-source software to the biomedical research community. Inaugurated in September 1999 under the auspices of the NIH's National Center for Research Resources (NCRR), PhysioNet provides an on-line forum for free dissemination and exchange of research data and software, with facilities for cooperative analysis of data and evaluation of new analytic methods. As of September 2000, PhysioBank, the data archive made available via PhysioNet, contained roughly 35 gigabytes of recorded signals and annotations. PhysioNet is a public service of the Research Resource for Complex Physiologic Signals, a cooperative project initiated by researchers at Boston's Beth Israel Deaconess Medical Center/Harvard Medical School, Boston University, McGill University, and MIT.
Glycation Products and the Pathogenesis of Diabetic Complications (1992)

Glucose irreversibly modifies long-lived macromolecules by forming AGEs as a function of glucose concentration and time. AGEs cause qualitative and quantitative changes in extracellular matrix components such as type IV collagen, laminin, and vitronectin. These AGE-induced changes can affect cell adhesion, growth, and matrix accumulation. AGE-modified proteins also alter cell function by interacting with specific receptors on macrophages and endothelial cells, inducing changes that promote matrix overproduction, focal thrombosis, and vasoconstriction. DNA and nuclear proteins also may be targets for AGE damage. The persistence of accumulated AGEs during periods of normal glucose homeostasis may explain the phenomenon of hyperglycemic memory. Pharmacological inhibition of in vivo AGE formation by aminoguanidine prevents or ameliorates diabetic retinopathy, nephropathy, and neuropathy in animal models. These data suggest that aminoguanidine and other AGE inhibitors have a potential therapeutic role in the treatment of diabetic patients.
Simian Immunodeficiency Virus SIVmac239 Infection of Major Histocompatibility Complex-Identical Cynomolgus Macaques from Mauritius (2006)

Nonhuman primates are widely used to study correlates of protective immunity in AIDS research. Successful cellular immune responses have been difficult to identify because heterogeneity within macaque major histocompatibility complex (MHC) genes results in quantitative and qualitative differences in immune responses. Here we use microsatellite analysis to show that simian immunodeficiency virus (SIV)-susceptible cynomolgus macaques (Macaca fascicularis) from the Indian Ocean island of Mauritius have extremely simple MHC genetics, with six common haplotypes accounting for two-thirds of the MHC haplotypes in feral animals. Remarkably, 39% of Mauritian cynomolgus macaques carry at least one complete copy of the most frequent MHC haplotype, and 8% of these animals are homozygous. In stark contrast, entire MHC haplotypes are rarely conserved in unrelated Indian rhesus macaques. After intrarectal infection with highly pathogenic SIVmac239 virus, a pair of MHC-identical Mauritian cynomolgus macaques mounted concordant cellular immune responses comparable to those previously reported for a pair of monozygotic twins infected with the same strain of human immunodeficiency virus. Our identification of relatively abundant SIV-susceptible, MHC-identical macaques will facilitate research into protective cellular immunity.
The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro (2020)

Cenicriviroc (CVC) is a small-molecule chemokine receptor antagonist with highly potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity through antagonizing C-C chemokine receptor type 5 (CCR5) as a coreceptor of HIV-1. CVC also strongly antagonizes C-C chemokine receptor type 2b (CCR2b), thereby it has potent anti-inflammatory and immunomodulatory effects. CVC is currently under clinical trials in the patients for treatment of nonalcoholic steatohepatitis, in which immune cell activation and dysregulation of proinflammatory cytokines play an important role in its pathogenesis. In this study, CVC was examined for its inhibitory effect on the replication of SARS-CoV-2, the causative agent of COVID-19, in cell cultures and found to be a selective inhibitor of the virus. The 50% effective concentrations of CVC were 19.0 and 2.9 μM in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively. Interestingly, the CCR5-specific antagonist maraviroc did not show any anti-SARS-CoV-2 activity. Although the mechanism of SARS-CoV-2 inhibition by CVC remains to be elucidated, CCR2b does not seem to be its target molecule. Considering the fact that the regulation of excessive immune activation is required to treat COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection.
Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions (2011)

Human aging is associated with bone loss leading to bone fragility and increased risk of fractures. The cellular and molecular causes of age-related bone loss are current intensive topic of investigation with the aim of identifying new approaches to abolish its negative effects on the skeleton. Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women beyond the fifth decade and results from two groups of pathogenic mechanisms: extrinsic mechanisms that are mediated by age-related changes in bone microenvironment including changes in levels of hormones and growth factors, and intrinsic mechanisms caused by the osteoblast cellular senescence. The aim of this review is to provide a summary of the intrinsic senescence mechanisms affecting osteoblastic functions and how they can be targeted to abolish age-related osteoblastic dysfunction and bone loss associated with aging.
hnRNP U interacts with the c-Myc-Max complex on the E-box promoter region inducing the ornithine decarboxylase gene (2009)

The promoter of the ornithine decarboxylase (ODC) gene contains two E-boxes, which are critical sites for transcriptional activation by the binding of c-Myc-Max heterodimers. We have identified heterogeneous nuclear ribonuclear protein U (hnRNP U) as a component of the complex formed on the E-box-containing promoter region of the ODC gene by using DNA-affinity chromatography, immunoprecipitation and chromatin immunoprecipitation assays. The N-terminal domain of hnRNP U was responsible for the association with c-Myc-Max complex. Down-regulation of hnRNP U with RNA interference blocked the induction of the ODC gene and cell growth by serum stimulation, suggesting that hnRNP U is a coactivator of the c-Myc-Max complex and essential for cell proliferation. Electrophoretic mobility-shift assays revealed that the segment between the two E-boxes in the promoter is the primary binding site of hnRNP U. The putative binding sequence was narrowed-down to a 13-nucleotide segment by comparing the sequence between the E-boxes with the binding sites of hnRNP U, which were recently identified in the promoter of Bmal1, a core component of the circadian molecular oscillator. These findings increase our knowledge of how the c-Myc-Max complex exerts its transcriptional regulatory role and suggest that hnRNP U may be a coactivator of this transcriptional activator complex.
Inhibition of murine dendritic cell activation by synthetic phosphorothioate oligodeoxynucleotides (2002)

Depending on sequence and backbone structure, DNA can inhibit as well as stimulate immune responses. As previously shown, single-base phosphorothioate (Ps) oligodeoxynucleotides (ODN) can inhibit murine macrophage activation. To determine whether these compounds can also affect dendritic cells (DC), the effects of 30-mer Ps ODN (SdA, SdT, SdG, and SdC) on DC activation were assessed in an in vitro system. With DC preparations obtained from murine bone marrow cultured in granulocyte macrophage-colony stimulating factor, the Ps ODN blocked the production of interleukin-12 and nitric oxide induced by bacterial DNA, an immunostimulatory cytosine phosphate guanosine dinucleotide (CpG) ODN and lipopolysaccharide (LPS). Furthermore, these compounds inhibited up-regulation of costimulatory molecules CD40 and CD86 as well as major histocompatibility complex-II molecules, indicating an effect on DC maturation. Although the Ps ODN limited uptake of CpG ODN as assessed by flow cytometry, the Ps ODN did not affect LPS uptake, suggesting that these compounds inhibit DC responses by effects on downstream signaling pathways. Together, these observations extend the range of action of inhibitory ODN to DC and suggest a role of these compounds as immunomodulatory agents.
Nootropic α7 nicotinic receptor allosteric modulator derived from GABA A receptor modulators (2007)

Activation of brain alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of alpha7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective alpha7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs. Compound 6 (N-(4-chlorophenyl)-alpha-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at alpha7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of alpha7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.
The mechanism of activation of 4-hydroxycyclophosphamide (1987)

4-Hydroxycyclophosphamide (2/3) of unknown stereochemistry is the initial metabolite formed after administration of cyclophosphamide (1). Ultimate conversion to the cytotoxic metabolite phosphoramide mustard (6) is initiated by ring opening of 4-hydroxycyclophosphamide to produce aldophosphamide (4). The ring-opening reaction and subsequent equilibration of 2-4 are subject to general-acid catalysis, and the equilibrium composition is independent of buffer structure and pH. In contrast, formation of 6 from 4 proceeds by general-base-catalyzed beta-elimination. trans-4-Hydroxycyclophosphamide undergoes ring opening ca. 4 times faster than the cis isomer, and cyclization of 4 favors the trans isomer by a factor of ca. 3 over the cis isomer. The rapid equilibration of 2-5 and the absence of elimination to give 6 at pH approximately 5 provides a convenient method to prepare a stable equilibrium mixture of activated cyclophosphamide metabolites suitable for in vitro use.
Preparation of pancreatic β-cells from human iPS cells with small molecules (2012)

Human induced pluripotent stem (iPS) cells obtained from patients are expected to be a useful source for cell transplantation therapy, because many patients (including those with type 1 diabetes and severe type 2 diabetes) are on waiting lists for transplantation for a long time due to the shortage of donors. At present, many concerns related to clinical application of human iPS cells have been raised, but rapid development of methods for the establishment, culture, and standardization of iPS cells will lead autologous cell therapy to be realistic sooner or later. However, establishment of a method for preparing some of desired cell types is still challenging. Regarding pancreatic β-cells, there have been many reports about differentiation of these cells from human embryonic stem (ES)/iPS cells, but a protocol for clinical application has still not been established. Since there is clear proof that cell transplantation therapy is effective for diabetes based on the results of clinical islet transplantation, pancreatic β-cells prepared from human iPS cells are considered likely to be effective for reducing the burden on patients. In this article, the current status of procedures for preparing pancreatic β-cells from human ES/iPS cells, including effective use of small molecules, is summarized, and some of the problems that still need to be overcome are discussed.
Mechanisms of oligozoospermia: an oxidative stress perspective (2014)

Infertile patients presenting with poor semen concentration, motility, and morphology have significantly higher levels of reactive oxygen species (ROS). In this cross-sectional study, our goal was to: 1) determine how semen parameters such as concentration, motility, morphology, as well as ROS are altered in oligozoospermic men alone and those in combination with poor sperm concentration, motility, morphology, and compare these with three control groups; unproven donors, donors with proven fertility <2 years, and proven donors with fertility established >2 years; 2) establish the cutoff, sensitivity, specificity for ROS, and see how it compared in the three donor groups compared to the patient groups, and 3) establish the reference range for the various semen parameters in these three donor groups compared to the oligozoospermic group by generating receiver operating characteristic (ROC) curves for each parameter. Fifty-six donors and 101 infertile men were included in this study. The patient group included: oligozoospermia: n = 16; oligoasthenozoospermia (OA): n = 12; oligoteratozoospermia (OT): n = 19; oligoasthenoteratozoospermia (OAT): n = 54. The patient group was compared with the three donor groups. Proven donors who had established a pregnancy in the past or recently (<2 years) had significantly improved semen motility and morphology compared to the OAT and OT groups (p < 0.001). In the OAT group, normal morphology was positively correlated with concentration and negatively with levels of ROS. Compared to the three donor groups, oligozoospermic patients in the OAT, OT, and OA groups had significantly elevated ROS levels. The cutoff for ROS in the proven donors < 2 years was significantly lower with a higher sensitivity and specificity compared to the unproven donors and donors who had not established a recent pregnancy. These results indicate a positive association between semen parameters and ROS suggesting a common underlying mechanism in these infertile patient groups.
Protein Dynamics and Enzymatic Catalysis:  Investigating the Peptidyl−Prolyl Cis−Trans Isomerization Activity of Cyclophilin A (2004)

A growing body of evidence suggests a connection between protein dynamics and enzymatic catalysis. In this paper, we present a variety of computational studies designed to investigate the role of protein dynamics in the detailed mechanism of peptidyl-prolyl cis-trans isomerization catalyzed by human cyclophilin A. The results identify a network of protein vibrations, extending from surface regions of the enzyme to the active site and coupled to substrate turnover. Indications are that this network may have a role in promoting catalysis. Crucial parts of this network are found to be conserved in 10 cyclophilin structures from six different species. Experimental evidence for the existence of this network comes from previous NMR relaxation studies, where motions in several residues, forming parts of this network, were detected only during substrate turnover. The high temperature factors (from X-ray crystal structures) associated with the network residues provide further evidence of these vibrations. Along with the knowledge of enzyme structure, this type of network could provide new insights into enzymatic catalysis and the effect of distant ligand binding on protein function. The procedure outlined in this paper is general and can be applied to other enzymatic systems as well. This presents an interesting opportunity; collaborative experimental and theoretical investigations designed to characterize in detail the nature and function of this type of network could enhance the understanding of protein dynamics in enzymatic catalysis.
Potency Stability of Recombinant (Serine-17) Human Interferon-β (1987)

The antiviral activity of Escherichia coli-derived (Serine-17) human interferon-beta, formulated with human serum albumin, is stable for 2 years when lyophilized and stored under refrigeration. This product shows an Arrhenius line fit for the stability of its activity when tested at multiple isothermal temperatures (25-80 degrees C). In both isothermal and nonisothermal elevated temperature studies, increasing the level of human serum albumin in the formulation results in increased thermal stability.
Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. (1987)

The antiproliferative and cytotoxic effects of 4-hydroxytamoxifen, an antiestrogen with a high affinity for the estrogen receptor, and of 17 beta-hydroxy-11 beta-(4-methylaminophenyl)-17-(1-propynyl)estra-4,9-dien-3- one-6-7 (RU486), an antiprogestin with a high affinity for the progestin receptor, have been studied on human breast cancer cell lines in culture. The number of dead cells was evaluated by several techniques (trypan blue stain exclusion, DNA cleavage, lactic dehydrogenase activity, morphological changes, and cloning efficiency in soft agar) and found to be increased both by the antiestrogen and the antiprogestin at concentrations correlating with the affinities for their respective receptors. This cytotoxic effect was prevented by the occupation of the respective receptors with estrogen and progestin and was not found in the estrogen receptor- and progestin receptor-negative MDA MB 231 and BT20 cell lines. The contrast between the ultrastructural modifications of chromatin and the integrity of mitochondria suggested that the antihormone-induced cell death was by apoptosis. We conclude that in addition to the receptor-mediated cytostatic activity and the nonspecific cytotoxic activity, antiestrogens trigger a third type of effect that we designate as "receptor-mediated cytotoxic." Similar conclusions can be drawn for the antiprogestin RU486, indicating moreover that the antihormone and antiproliferative activities of this drug are clearly dissociated. The mechanism of these receptor-mediated cytotoxic activities of antiestrogen and antiprogesterone is not known but does not seem to be explained entirely by the antihormone activity of these drugs.
Low interface trap density for remote plasma deposited SiO2 on n-type GaN (1996)

Metal-oxide-semiconductor capacitors were prepared with remote plasma-enhanced chemical vapor deposition of SiO2 at ∼300 °C on an n-type GaN epitaxial layer grown by atmospheric pressure metalorganic chemical-vapor deposition on a sapphire substrate. No hysteresis was observed in the high-frequency capacitance-voltage (C−V) measurements, and the measured C−V curve agreed with the C−V behavior calculated for an ideal oxide with the same flat-band voltage as the measured C–V curve. The absence of hysteresis and stretchout in the measured C–V curve and the increase of capacitance with incident ultraviolet light while in deep depletion suggest a low concentration of interface traps. These results demonstrate previous predictions of the absence of Fermi-level stabilization at the interface for the ionic crystal GaN.