gebhart/patrepeval huggingface dataset:
Channeling of extramitochondrial ornithine to matrix ornithine transcarbamylase. (1987)

In the presence of citrulline synthesis, we made the following observations. External ornithine is channeled between its transporter and ornithine transcarbamylase; mitochondria preloaded with cold ornithine, then incubated with [3H]ornithine, produced citrulline of the same specific radioactivity as that of external ornithine, while matrix ornithine remained essentially unlabeled. The channeling of ornithine suggests that some soluble enzymes are organized within the mitochondrial matrix. The rate of ornithine transport can be greater than 80 nmol/min/mg. At rates of carbamyl phosphate synthesis of 10-50 nmol/min/mg, the rate of citrulline synthesis is controlled by external ornithine in the range 0.03-0.2 mM; at greater than or equal to 0.2 mM ornithine, transport is not limiting for citrulline synthesis. At external ornithine concentrations less than or equal to 1 mM, i.e. within the physiological range, this amino acid is undetectable in the matrix. Given the rates of citrulline and urea synthesis which occur in vivo and the concentrations of ornithine present in the liver, our findings indicate that ornithine may contribute to the physiological regulation of urea synthesis. Preliminary reports of parts of this work have been published (Raijman, L., Cheung, C-W., and Cohen, N. S. (1984) Fed. Proc. 43, 1831; Cohen, N. S., Cheung, C-W., and Raijman, L. (1986) Fed. Proc. 45, 2677).
Specific Inhibition of AQP1 Water Channels in Isolated Rat Intrahepatic Bile Duct Units by Small Interfering RNAs (2003)

Cholangiocytes express water channels (i.e. aquaporins (AQPs)), proteins that are increasingly recognized as important in water transport by biliary epithelia. However, direct functional studies demonstrating AQP-mediated water transport in cholangiocytes are limited, in part because of the lack of specific AQP inhibitors. To address this issue, we designed, synthesized, and utilized small interfering RNAs (siRNAs) selective for AQP1 and investigated their effectiveness in altering AQP1-mediated water transport in intrahepatic bile duct units (IBDUs) isolated from rat liver. Twenty-four hours after transfection of IBDUs with siRNAs targeting two different regions of the AQP1 transcript, both AQP1 mRNA and protein expression were inhibited by 76.6-92.0 and 57.9-79.4%, respectively. siRNAs containing the same percent of base pairs as the AQP1-siRNAs but in random sequence (i.e. scrambled siRNAs) had no effect. Suppression of AQP1 expression in cholangiocytes resulted in a decrease in water transport by IBDUs in response to both an inward osmotic gradient (200 mosm) or a secretory agonist (forskolin), the osmotic water permeability coefficient (P(f)) decreasing up to 58.8% and net water secretion (J(v)) decreasing up to 87%. A strong correlation between AQP1 protein expression and water transport in IBDUs transfected with AQP1-siRNAs was consistent with the decrease in water transport by IBDUs resulting from AQP1 gene silencing by AQP1-siRNAs. This study is the first to demonstrate the feasibility of utilizing siRNAs to specifically reduce the expression of AQPs in epithelial cells and provides direct evidence of the contribution of AQP1 to water transport by biliary epithelia.
Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy (1996)

Previously, we have shown that both T and B lymphocytes from chronically nicotine-treated (NT) animals exhibit tolerance to activation by Ags (ligation of Ag receptors), as indicated by their decreased ability to mobilize intracellular calcium and, at least in T cells, arrest of cells in the G0/G1 phase of the cell cycle. Herein, we demonstrate that NT T cells significantly lose their ability to up-regulate inositol trisphosphate synthesis in response to TCR ligation or nonspecific activation of G proteins by AIF-4. However, increases in cAMP concentrations of T cells following activation of G protein-sensitive adenylate cyclase by cholera or pertussis toxin were not significantly affected by the nicotine treatment. Interestingly, compared with control T cells, the background levels of inositol trisphosphate were significantly elevated in NT T cells, indicating some degree of activation in these cells. This inference was further supported by observations that naive T cells from NT animals exhibit tyrosine phosphorylation of several substrates, including phospholipase C-gamma1, which were either absent or underphosphorylated in unstimulated control T cells. Moreover, when, after 4-wk nicotine treatment, nicotine pumps were removed and serum cotinine levels fell to background, inhibition of the Ab-forming cells and Ca2+ responses continued for at least 2 more wk. These results suggest that chronic in vivo nicotine exposure leads to T cell anergy and may contribute to nicotine/cigarette smoke-induced immunosuppression.
Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells (2016)

Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all-trans-retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down- or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor α (RARα) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARα agonists in AML cells. Moreover, in cells with a high basal level of RARα protein, the VDR gene is transcriptionally repressed as long as RARα agonist is absent. In these cells down-regulation of the level of RARα leads to increased expression of VDR. We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1,25D.
<title>Highly efficient AlGaN-based UV-LEDs and their application as visible light sources</title> (2002)

AlGaN-based highly efficient ultraviolet light emitting diodes (UV-LEDs) are reported. To enhance radiative recombination by suppressing the effect of the internal polarization field, we introduced an AlGaN quantum well as thin as 8 molecular layers, at which the optical transition is kept spatially direct. To improve the transparency and conductivity of p-type cladding layers, we introduced a short-period alloy superlattice. For stronger carrier confinement, high-Al-content carrier blocking layers are introduced. Further, to reduce nonradiative centers, we used high-quality bulk GaN substrate obtained by hydride vapor phase epitaxy (HVPE). The resultant UV-LED performance is intrinsically ideal. The maximum output power is 10mW at the injection current of 400 mA in spite of the optically absorptive GaN substrate, and the estimated internal quantum efficiency is over 80% at the wavelength of 352 nm. This wavelength has affords efficient excitation of fluorescent materials. We also demonstrate simultaneous and equivalent excitation of fluorescence material of three basal colors by this UV-LED.
Evidence for the Involvement of Tiam1 in Axon Formation (2001)

In cultured neurons, axon formation is preceded by the appearance in one of the multiple neurites of a large growth cone containing a labile actin network and abundant dynamic microtubules. The invasion-inducing T-lymphoma and metastasis 1 (Tiam1) protein that functions as a guanosine nucleotide exchange factor for Rac1 localizes to this neurite and its growth cone, where it associates with microtubules. Neurons overexpressing Tiam1 extend several axon-like neurites, whereas suppression of Tiam1 prevents axon formation, with most of the cells failing to undergo changes in growth cone size and in cytoskeletal organization typical of prospective axons. Cytochalasin D reverts this effect leading to multiple axon formation and penetration of microtubules within neuritic tips devoid of actin filaments. Taken together, these results suggest that by regulating growth cone actin organization and allowing microtubule invasion within selected growth cones, Tiam1 promotes axon formation and hence participates in neuronal polarization.
Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients (2017)

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8<sup>+</sup> tumor-infiltrating lymphocytes (TIL) and compared them with those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8<sup>+</sup> TILs compared with CD8<sup>+</sup> PBLs (<i>P</i> = 0.008 and <i>P</i> = 0.02, respectively). This increased CD8<sup>+</sup> TIL population coexpressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8<sup>+</sup> TILs. Indeed, the increased frequency of PD-1<sup>+</sup> and TIM-3<sup>+</sup> CD8<sup>+</sup> TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8<sup>+</sup> T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8<sup>+</sup> TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. <i>Cancer Immunol Res; 5(5); 408-16. ©2017 AACR</i>.
A video pre/post-processing LSI for video capture (1996)

A video processing LSI which converts video signals to digital YUV signals in various image formats was successfully developed for a video capture system. This LSI is suitable for PC cameras, camera/recorders and PC video capture boards.
MicroRNA expression profiles predictive of human renal allograft status (2009)

Immune rejection of organ transplants is a life-threatening complication and is exemplified by alterations in the expression of protein-encoding genes. Because microRNAs (miRNAs) regulate the expression of genes implicated in adaptive immunity, we investigated whether acute rejection (AR) is associated with alterations in miRNA expression within allografts and whether expression profiles are diagnostic of AR and predict allograft function. Seven of 33 renal allograft biopsies (12 AR and 21 normal) were profiled using microfluidic cards containing 365 mature human miRNAs (training set), and a subset of differentially expressed miRNAs were quantified in the remaining 26 allograft biopsies (validation set). We found a strong association between intragraft expression of miRNAs and messenger RNAs (mRNAs), and that AR, and renal allograft function, could be predicted with a high level of precision using intragraft levels of miRNAs. Our investigation of miRNA expression in normal human peripheral blood mononuclear cells (PBMCs) showed that miRNAs (miR-142-5p, -155, and -223) overexpressed in AR biopsies are highly expressed in PBMCs, and that stimulation with the mitogen phytohaemagglutinin results in an increase in the abundance of miR-155 and a decrease in miR-223 and let-7c. Quantification of miRNAs in primary cultures of human renal epithelial cells (HRECs) showed that miR-30a-3p, -10b, and let-7c are highly expressed in HRECs, and that stimulation results in a decreased expression of miR-30a-3p. Our studies, in addition to suggesting a cellular basis for the altered intragraft expression of miRNAs, propose that miRNA expression patterns may serve as biomarkers of human renal allograft status.
Protein Engineering Strategies for Designing More Stable Hemoglobin-based Blood Substitutes (1997)

Over the past five years our laboratory has been using rational, comparative, and random combinatorial mutagenesis strategies to optimize the alpha and beta subunits of recombinant human hemoglobin (Hb) for efficient O2 transport, greater stability, and minimum interference with vascular activity. In each approach, mammalian myoglobin (Mb) has been used as a prototype to develop experimental methodologies and to study the stereochemical mechanisms that govern O2 affinity, discrimination against CO, rates of ligand binding, auto- and chemically induced oxidation, resistance to hemin loss, and stability to globin denaturation. Multiple replacements in the distal portion of the heme pocket have been designed rationally to lower oxygen affinity and at the same time inhibit oxidative side reactions. The P50 values are adjusted by altering electrostatic and steric interactions between the bound ligand and residues at the Leu(B10), His(E7), and Va(E11) positions. Large apolar residues (Leu, Phe, Trp) at the B10 and E11 positions inhibit NO-induced and autooxidation in both myoglobin and hemoglobin by excluding oxidants and proton donors from the immediate vicinity of the bound ligand. Similar strategies appear to have evolved in a number of animal myoglobins and hemoglobins which have unusual amino acids at the E7, B10, and E11 positions. Random combinatorial mutagenesis techniques have been developed to insert new amino acid combinations near the bound ligand in sperm whale Mb. The objective is to obtain "unnatural" distal pocket structures that enhance O2 transport and resistance to oxidation by alternative mechanisms.
Immunologic Analysis of a Spinal Cord–Biopsy Specimen from a Patient with Human T-Cell Lymphotropic Virus Type I–Associated Neurologic Disease (1997)

Human T-cell lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia and a chronic progressive neurologic disease, HTLV-I–associated myelopathy–tropical spastic paraparesis (hereafter referred to as HTLV-I–associated myelopathy).1–5 HTVL-I is endemic in Japan, the Caribbean, Africa, and South America.5 Risk factors for infection include sexual contact, exchange of blood products, and vertical transmission from mother to child.5 HTLV-I–associated myelopathy causes progressive myelopathy with atrophy of the spinal cord.5,6 Subcortical white-matter lesions are sometimes present on magnetic resonance imaging.5–7 Cerebrospinal fluid shows pleocytosis, elevated titers of IgG, and oligoclonal bands.8–10 Autopsy results correlate with neurologic findings . . .
Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer (2011)

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.
Vascular Cell Adhesion Molecule-1 Is Expressed by Cortical Thymic Epithelial Cells and Mediates Thymocyte Adhesion. Implications for the Function of α4β1 (VLA4) Integrin in T-Cell Development (1997)

T-cell development requires a series of discrete selection and activation signals delivered to maturing progenitors in the thymic cortex and medulla. We have previously shown the constitutive activity of the integrin, alpha4beta1 (VLA4), on a unique subpopulation of immature cortical thymocytes and proposed a role for integrin-mediated adhesion in positive selection by cortical epithelium. In the present report we show that thymic epithelial cell lines express vascular cell adhesion molecule-1 (VCAM-1) a high-affinity ligand for apha4beta1, and that VCAM-1 mediates thymocyte binding to these lines. Immunohistochemistry and confocal microscopy show that VCAM-1 is selectively expressed in situ by thymic epithelium in the cortex and corticomedullary junction, two locations at which VCAM-1 could determine the interaction between immature thymocytes and selecting elements on epithelial cells. In parallel, we confirmed that fibronectin (FN), the alternative ligand for alpha4beta1, is expressed predominantly in the medulla. These results suggest that VCAM-1 is an adhesive ligand in the thymic cortex for the activated form of alpha4beta1 constitutively expressed during development by immature double positive thymocytes. The structural segregation of the alternative ligand, FN, to the medulla suggests that medullary FN may regulate the migration, development, and export of more mature thymocytes.
The receptor-binding domain of human alpha 2-macroglobulin. Isolation after limited proteolysis with a bacterial proteinase. (1986)

Limited proteolysis of human alpha 2-macroglobulin (alpha 2M) by a novel bacterial proteinase resulted in the isolation of a soluble 20-kDa domain. The isolated fragment contained the receptor recognition site, expressed on alpha 2M complexes, as it competed effectively with alpha 2M-trypsin for binding to the receptor on skin fibroblasts. The fragment also reacted with two monoclonal antibodies which define epitopes that are part of the receptor recognition site. Characterization of the 20-kDa domain showed it to contain an intact disulfide bridge, while its susceptibility to N-glycanase and reaction with concanavalin A indicated the presence of N-linked carbohydrate. The NH2-terminal sequence (Glu-Glu-Phe-Pro-Phe-Ala-Leu-Gly-Val-Glu-Thr-Leu-Pro-Glu-Thr-Cys-Asp-Glu -Pro) proved this fragment to constitute the COOH terminus of human alpha 2M. Proteolysis occurred at Lys1313-Glu which together with the observation that tosyllysine chloromethyl ketone was an effective inhibitor of the bacterial proteinase, would indicate the latter to hydrolyze preferentially peptide bonds carboxyl-terminal to lysine residues.
Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase (2009)

The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T(FH)) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T(FH) generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4(+) T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T(FH) cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T(FH) and suggest that CD28 and ICOS play differential roles during a multistep process of T(FH) differentiation.
DBN based multi-stream models for audio-visual speech recognition (2004)

In this paper, we propose a model based on dynamic Bayesian networks (DBN) to integrate information from multiple audio and visual streams. We also compare the DBN based system (implemented using the Graphical Model Toolkit (GMTK)) with a classical HMM (implemented in the Hidden Markov Model Toolkit (HTK)) for both the single and two stream integration problems. We also propose a new model (mixed integration) to integrate information from three or more streams derived from different modalities and compare the new model's performance with that of a synchronous integration scheme. A new technique to estimate stream confidence measures for the integration of three or more streams is also developed and implemented. Results from our implementation using the Clemson University Audio Visual Experiments (CUAVE) database indicate an absolute improvement of about 4% in word accuracy in the -4 to 10db average case when making use of two audio and one video streams for the mixed integration models over the sychronous models.
A ROBUST ALKALINE-SIDE CSEX SOLVENT SUITABLE FOR REMOVING CESIUM FROM SAVANNAH RIVER HIGH LEVEL WASTE# (2000)

ABSTRACT A robust solvent suitable for extracting cesium from alkaline nitrate media like that of the high-level liquid waste stored at the U.S. Department of Energy Savannah River Site has been developed. The solvent is composed of the cesium extractant calix[4]arene-bis-(tert-octylbenzo-crown-6) (“BOBCalixC6”) at 0.01 M, the modifier l-(2,2,3,3-tetrafluoropropoxy)-3-(4-sec-butylphenoxy)-2-propanol (“Cs-7SBT”) at 0.50 M, trioctylamine (“TOA”) at 0.001 M, and the aliphatic diluent Isopar® L. The solvent holds up exceptionally well under various stresses, such as sustained contact with waste simulant and dilute nitric acid; repeated extraction, scrubbing, and stripping cycles; and excessive loading. The behavior of the solvent in batch-equilibrium flowsheet tests conducted at 15, 25, and 45 °C is presented. Flowsheet calculations show that the Savannah River Site requirements for a decontamination factor of 40,000 and a cesium concentration factor of 12 could be met in a 22-stage bank of 25-cm centrifugal contactors at 25 °C with conservative assumptions regarding hydrodynamics and stage efficiency. Exploiting the temperature dependence of extraction and stripping could reduce the number of stages to 18.