gebhart/patrepeval huggingface dataset:
In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8 + T cell inflammation (2010)

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8(+) T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214) in gene-targeted nonobese diabetic (NOD) mice expressing a T cell "invisible" IGRP(206-214) sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP(206-214)-reactive CD8(+) T cells. Conversely, IGRP(206-214)-reactive, but not nonautoreactive CD8(+) T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8(+) T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8(+) T cells contained in extralymphoid autoimmune lesions are largely autoreactive.
The high molecular weight receptor to transforming growth factor-beta contains glycosaminoglycan chains. (1988)

Proteoglycans are constituents of the cell surface that may play important roles in the regulation of cell behavior. Here we report that the 250-kDa receptor subunit that binds the multifunctional protein, transforming growth factor-beta 1 (TGF-beta 1), contains chains of heparan sulfate and chondroitin sulfate and thus is a proteoglycan. Digestion of TGF-beta 1-receptor complexes with glycosaminoglycan (GAG)-specific degradative enzymes yield core proteins of 115-140 kDa. Cell monolayers that had been predigested with GAG-specific degradative enzymes were capable of binding high levels of TGF-beta 1, but the size of the binding components was shifted from the high molecular weight species to the lower molecular weight core proteins, indicating that GAG chains are not necessary for TGF-beta 1 binding to the cell. The presence of GAG chains on the receptor subunit indicates that it has the potential for interaction with the extracellular matrix.
The Central Executioner of Apoptosis: Multiple Connections between Protease Activation and Mitochondria in Fas/APO-1/CD95- and Ceramide-induced Apoptosis (1997)

According to current understanding, cytoplasmic events including activation of protease cascades and mitochondrial permeability transition (PT) participate in the control of nuclear apoptosis. However, the relationship between protease activation and PT has remained elusive. When apoptosis is induced by cross-linking of the Fas/APO-1/CD95 receptor, activation of interleukin-1beta converting enzyme (ICE; caspase 1) or ICE-like enzymes precedes the disruption of the mitochondrial inner transmembrane potential (DeltaPsim). In contrast, cytosolic CPP32/ Yama/Apopain/caspase 3 activation, plasma membrane phosphatidyl serine exposure, and nuclear apoptosis only occur in cells in which the DeltaPsim is fully disrupted. Transfection with the cowpox protease inhibitor crmA or culture in the presence of the synthetic ICE-specific inhibitor Ac-YVAD.cmk both prevent the DeltaPsim collapse and subsequent apoptosis. Cytosols from anti-Fas-treated human lymphoma cells accumulate an activity that induces PT in isolated mitochondria in vitro and that is neutralized by crmA or Ac-YVAD.cmk. Recombinant purified ICE suffices to cause isolated mitochondria to undergo PT-like large amplitude swelling and to disrupt their DeltaPsim. In addition, ICE-treated mitochondria release an apoptosis-inducing factor (AIF) that induces apoptotic changes (chromatin condensation and oligonucleosomal DNA fragmentation) in isolated nuclei in vitro. AIF is a protease (or protease activator) that can be inhibited by the broad spectrum apoptosis inhibitor Z-VAD.fmk and that causes the proteolytical activation of CPP32. Although Bcl-2 is a highly efficient inhibitor of mitochondrial alterations (large amplitude swelling + DeltaPsim collapse + release of AIF) induced by prooxidants or cytosols from ceramide-treated cells, it has no effect on the ICE-induced mitochondrial PT and AIF release. These data connect a protease activation pathway with the mitochondrial phase of apoptosis regulation. In addition, they provide a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.
Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues (2007)

Periostin is predominantly expressed in collagen-rich fibrous connective tissues that are subjected to constant mechanical stresses including: heart valves, tendons, perichondrium, cornea, and the periodontal ligament (PDL). Based on these data we hypothesize that periostin can regulate collagen I fibrillogenesis and thereby affect the biomechanical properties of connective tissues. Immunoprecipitation and immunogold transmission electron microscopy experiments demonstrate that periostin is capable of directly interacting with collagen I. To analyze the potential role of periostin in collagen I fibrillogenesis, gene targeted mice were generated. Transmission electron microscopy and morphometric analyses demonstrated reduced collagen fibril diameters in skin dermis of periostin knockout mice, an indication of aberrant collagen I fibrillogenesis. In addition, differential scanning calorimetry (DSC) demonstrated a lower collagen denaturing temperature in periostin knockout mice, reflecting a reduced level of collagen cross-linking. Functional biomechanical properties of periostin null skin specimens and atrioventricular (AV) valve explant experiments provided direct evidence of the role that periostin plays in regulating the viscoelastic properties of connective tissues. Collectively, these data demonstrate for the first time that periostin can regulate collagen I fibrillogenesis and thereby serves as an important mediator of the biomechanical properties of fibrous connective tissues.
Expression of Elf-1 and survivin in non-small cell lung cancer and their relationship to intratumoral microvessel density (2010)

The expression of Elf-1 and survivin in NSCLC is related to differentiation, lymphatic metastasis, clinical stage, and prognosis, and both are positively correlated with iMVD. Detection their combined expression can help to predict the malignant behavior of NSCLC. Blocking the activity of Elf-1 and survivin may be a new way to inhibit angiogenesis in NSCLC.
Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation (2001)

There is no reliable laboratory indicator of the onset of chronic graft-versus-host disease (cGVHD). This study looks at whether the expression of OX40, a member of the tumor necrosis factor receptor family, is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplantation. Peripheral blood mononuclear cells from 22 patients after day 100 were subjected to multicolor flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+ T cells were significantly higher in patients with cGVHD than those without (P <.0001 and P =.001, respectively). Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and closely correlated with the therapeutic response. The expression of CD25, CD69, and HLA-DR was partially detectable on OX40+ T cells. These results indicate that serial measurement of OX40+ T cells is useful for predicting the onset as well as the therapeutic response of cGVHD and raise a possibility that the OX40/gp34 system is involved in the pathogenesis of cGVHD.
Purification and characterization from bovine brain cytosol of a novel regulatory protein inhibiting the dissociation of GDP from and the subsequent binding of GTP to rhoB p20, a ras p21-like GTP-binding protein. (1990)

A novel regulatory protein for the rho proteins (rhoA p21 and rhoB p20), belonging to a ras p21/ras p21-like small molecular weight (Mr) GTP-binding protein (G protein) superfamily, was purified to near homogeneity from bovine brain cytosol and characterized. This regulatory protein, designated here as GDP dissociation inhibitor (GDI) for the rho proteins (rho GDI), inhibited the dissociation of GDP from rhoB p20 and the binding of guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) to the GDP-bound form of rhoB p20 but not of that to the guanine nucleotide-free form. The Mr value of rho GDI was estimated to be about 27,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and from the S value, indicating that rho GDI is composed of a single polypeptide without a subunit structure. The isoelectric point was about pH 5.7. rho GDI made a complex with the GDP-bound form of rhoB p20 with a molar ratio of 1:1 but not with the GTP gamma S-bound or guanine nucleotide-free form. rho GDI did not stimulate the GTPase activity of rhoB p20 and by itself showed neither GTP gamma S-binding nor GTPase activity. rho GDI was equally active for rhoA p21 and rhoB p20 but was inactive for other ras p21/ras p21-like G proteins including c-Ha-ras p21, smg p25A, and smg p21. rho GDI activity was detected in the cytosol fraction of various rat tissues. These results indicate that, in mammalian tissues, there is a novel type of regulatory protein specific for the rho proteins that interacts with the GDP-bound form of the rho proteins and thereby regulates the GDP/GTP exchange reaction of the rho proteins by inhibiting the dissociation of GDP from and the subsequent binding of GTP to them. Since there is a GTPase-activating protein for the rho proteins stimulating the GTPase activity of the rho proteins in mammalian tissues, the rho proteins appear to be regulated at least by GTPase-activating protein and GDI in a dual manner.
A mechanism for the HLA-A*01–associated risk for EBV+ Hodgkin lymphoma and infectious mononucleosis (2008)

To the editor:

Expression of the common class I human leukocyte antigen (HLA) A*01 has recently been shown to increase the risk of developing Epstein-Barr virus (EBV)–positive Hodgkin lymphoma (HL).[1][1] Furthermore, genetic markers closely linked to the HLA-A*01 allele were also shown to be
Control of CREB-binding Protein Signaling by Nuclear Fibroblast Growth Factor Receptor-1 (2005)

In integrative nuclear fibroblast growth factor receptor-1 (FGFR1) signaling a newly synthesized FGFR1 translocates to the nucleus to stimulate cell differentiation and associated gene activities. The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth. Cell differentiation and gene activation by nuclear FGFR1 do not require tyrosine kinase activity. Instead, FGFR1 stimulates transcription in cooperation with CBP by increasing recruitment of RNA polymerase II and histone acetylation at the active gene promoter. FGFR1 is a multifactorial protein whose N terminus interacts with CBP and C terminus with ribosomal S6 kinase 1 (RSK1). Nuclear FGFR1 augments CBP-mediated transcription by 1) releasing the CBP C-terminal domain from RSK1 inhibition and 2) activating the CBP N-terminal domain. The interaction of FGFR1 with CBP and RSK1 allows activation of gene transcription and may play a role in cell differentiation.
Clinical pharmacological study of a plasma‐derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors – Phase I trial (2011)

MC710, a combined product of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non-bleeding state. This was a multi-centre, open-labelled, non-randomized, active controlled crossover, dose-escalation study of five doses (20-120 μg kg(-1) of FVIIa) with re-administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 μg kg(-1)) and/or FEIBA (50 and 75 U kg(-1)) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (C(max)) of MC710 active ingredients increased dose-dependently within the range of 20 and 120 μg kg(-1). After administration of MC710, activated partial thromboplastin time (APTT) was dose-dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 μg kg(-1).
Antibodies against the antibiotics: an overview. (1991)

Antibiotics are small molecules used in the treatment of diseases due to pathogenic microorganisms such as bacteria, viruses, fungi. They have different mechanisms of actions and by exploiting their selective toxicity on the infecting microorganism they do not necessarily damage the host cell. Assay for antibiotic concentrations in blood, urine and other body fluids is motivated primarily in conjunction with antibiotic pharmacology and pharmacokinetics to: a) establish the therapeutic levels of the drug; b) monitor antibiotics with narrow toxic/therapeutic ratios; c) detect accumulation of the antibiotic metabolites. The assay used to measure a wide variety of antibiotics is based on the intrinsic capability of these molecules to inhibit the growth of a suitable microorganism. In the last few years other types of tests, e.g., enzyme immunoassays, have been developed based on polyclonal and monoclonal antibodies. Antibodies against non antigenic molecules like antibiotics can be raised by using as antigen the antibiotic (hapten), conjugated with a carrier protein. Polyclonal antibodies containing mixed populations of antibodies (against different antigenic sites of the hapten, the carrier and the site of conjunction between the hapten and the carrier) are largely used to set up enzyme immunoassays for antibiotics. Monoclonal antibodies by recognizing one antigenic site of the hapten have a better specificity but sometimes less affinity than polyclonals. In the case of antibiotics, to raise monoclonal antibodies with good affinity it is important to use targeted immunization and screening strategies that utilize the antibiotic conjugated in different ways to different carriers.(ABSTRACT TRUNCATED AT 250 WORDS)
Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design (2020)

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the <i>de novo</i> design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, <i>in vivo</i> efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.
Glutamate infused posttraining into the hippocampus or caudate-putamen differentially strengthens place and response learning (1999)

A cross-maze task that can be acquired through either place or response learning was used to examine the hypothesis that posttraining neurochemical manipulation of the hippocampus or caudate-putamen can bias an animal toward the use of a specific memory system. Male Long-Evans rats received four trials per day for 7 days, a probe trial on day 8, further training on days 9-15, and an additional probe trial on day 16. Training occurred in a cross-maze task in which rats started from a consistent start-box (south), and obtained food from a consistent goal-arm (west). On days 4-6 of training, rats received posttraining intrahippocampal (1 microgram/0.5 microliter) or intracaudate (2 microgram/0.5 microliter) injections of either glutamate or saline (0.5 microliter). On days 8 and 16, a probe trial was given in which rats were placed in a novel start-box (north). Rats selecting the west goal-arm were designated "place" learners, and those selecting the east goal-arm were designated "response" learners. Saline-treated rats predominantly displayed place learning on day 8 and response learning on day 16, indicating a shift in control of learned behavior with extended training. Rats receiving intrahippocampal injections of glutamate predominantly displayed place learning on days 8 and 16, indicating that manipulation of the hippocampus produced a blockade of the shift to response learning. Rats receiving intracaudate injections of glutamate displayed response learning on days 8 and 16, indicating an accelerated shift to response learning. The findings suggest that posttraining intracerebral glutamate infusions can (i) modulate the distinct memory processes mediated by the hippocampus and caudate-putamen and (ii) bias the brain toward the use of a specific memory system to control learned behavior and thereby influence the timing of the switch from the use of cognitive memory to habit learning to guide behavior.
<title>Pattern recognition by optical neural network based on the optical correlator</title> (1993)

The possibilities of the optical neural network formed by placing the optical correlator in a linear resonator to realize the vectors comparison and image preparation are discussed. The adaptive neural network model to pattern recognize on the complex background is proposed. The optical implementation of that NN model is discussed.
Interaction of p53 with MDM2 is independent of E6 and does not mediate wild type transformation suppressor function. (1994)

Using a new series of p53 mutants targeting the conserved regions we have analysed the relationship of various activities of the protein. Mdm-2 and human papillomavirus (HPV) E6, two proteins which interact with and abrogate p53 function, were shown to bind independently. Deletion of the conserved regions of the protein in which most of the naturally occurring mutations are found (boxes II-V) abrogated transcriptional activity and the ability to interact with E6, supporting the importance of this DNA binding domain to these activities. Nevertheless, these mutants retained the ability to interact with mdm2. One mutant, deleted of all the C-terminal sequences, showed loss of mdm2 binding, E6 binding and transcriptional activity. More subtle mutations within the C-terminus of the protein, including alterations of the cdc2 and CKII phosphorylation sites, had no effect on the transcriptional trans-activation, mdm-2 or E6 binding functions, indicating that phosphorylation of these sites is not essential for these activities. Deletion of conserved box I sequences abolished the interaction with mdm-2 without loss of transcriptional activation or transformation suppressor activity, suggesting that mdm-2 is not a downstream effector of p53 function.
Development of phosphors with high thermal stability and efficiency for phosphor-converted LEDs (2014)

This article briefly reviews the developments of the phosphors with high thermal stability and high efficiency for use in phosphor-converted LED (pcLED) packages by Lightscape Materials Inc. (wholly owned by The Dow Chemical Company). The current industry design objectives for pcLED packages are first outlined with emphasis on the emission spectral features required for target brightness and color characteristics for general illumination and back light unit for liquid crystal displays. There is a growing demand on thermal stability of the phosphor emission as the LED package power increases. A phenomenological analysis is described on luminescence loss and its relation to thermal stability of luminescence emission at elevated temperatures, which serves as an empirical guide in the search for new phosphor materials of high thermal stability. Finally, the formulations and luminescence properties of the proprietary carbidonitride and oxycarbidonitride phosphors are discussed.
Twisted molecular magnets (2011)

The use of derivatised salicylaldoximes in manganese chemistry has led to the synthesis of a family of approximately fifty hexanuclear ([Mn(III)(6)]) and thirty trinuclear ([Mn(III)(3)]) Single-Molecule Magnets (SMMs). Deliberate, targeted structural distortion of the metallic core afforded family members with increasingly puckered configurations, leading to a switch in the pairwise magnetic exchange from antiferromagnetic to ferromagnetic. Examination of both the structural and magnetic data revealed a semi-quantitative magneto-structural correlation, from which the factors governing the magnetic properties could be extracted and used for predicting the properties of new family members and even more complicated structures containing analogous building blocks. Herein we describe an overview of this extensive body of work and discuss its potential impact on similar systems.
Emerging role of vasopressin. (2006)

Ionotropic agents are frequently used in vasodilatory shock like conditions of septic or nonseptic origin. Conventional catecholamines such as norepinephrine are used at a very high dose with possibility of adverse effects in many patients. One often encounters refractoriness to these drugs. Infusion of vasopressin (VP) which is detectable at inappropriately low level in advanced phase of septic shock might allow withdrawal of catecholamines, as it maintains adequate mean arterial pressure (MAP), improves urine output and leaves perfusion of vital organs unhindered. Vasopressin has been found to be superior to epinephrine in animal models and some human trials, especially in patients with resistant ventricular fibrillation (VF) while doing cardiopulmonary resuscitation (CPR). Analogues of VP have also been used for diuresis in patients of hepatorenal syndrome.