gebhart/patrepeval huggingface dataset:
γ-Atrial Natriuretic Polypeptide (γANP)-Derived Peptides in Human Plasma: Cosecretion of N-TerminalγANP Fragment andαANP* (1988)

Using RIAs for the N- and C-terminal fragments of the human atrial natriuretic polypeptide (ANP) precursor gamma ANP, that is gamma ANP-(1-25), and alpha ANP [gamma ANP-(99-126)], we studied the secretion of gamma ANP-derived peptides from the heart in normal subjects and patients with heart disease, chronic renal failure, and cirrhosis. We detected gamma ANP-(1-25)-like immunoreactivity (-LI) in plasma from normal subjects (n = 17) in considerable amounts [mean, 510 +/- 62 (+/- SE) pg/mL (174 +/- 21 pmol/L)]; the mean plasma alpha ANP-LI level at the same time in these subjects was 32.8 +/- 4.4 pg/mL (10.7 +/- 1.4 pmol/L). Gel permeation chromatographic analysis of plasma samples from normal subjects and patients with heart disease and chronic renal failure revealed two major components; one was alpha ANP, and the other was the 10K N-terminal gamma ANP fragment (N-peptide) resulting from the removal of alpha ANP (3K) from gamma ANP (13K). In addition, gamma ANP (13K), which possessed both gamma ANP-(1-25)-LI and alpha ANP-LI, and beta ANP, an antiparallel dimer of alpha ANP, were detected in some patients as minor components. A significant positive correlation between plasma levels of the N-terminal gamma ANP fragment and alpha ANP (P less than 0.01) and almost equal step-ups in the coronary sinus plasma levels of the N-terminal gamma ANP fragment and alpha ANP suggest that they are cosecreted in equimolar amounts. The high molar ratio of plasma gamma ANP-(1-25)-LI to alpha ANP-LI (17.4 +/- 1.4) in normal subjects and the significantly higher ratio in patients with chronic renal failure (36.9 +/- 7.1; P less than 0.01) suggest the slower clearance of the N-terminal gamma ANP fragment than alpha ANP and a role for the kidney in its degradation. Since the molar ratio of plasma gamma ANP-(1-25)-LI to alpha ANP-LI in patients with cirrhosis (20.7 +/- 2.7) was similar to that in normal subjects, it is unlikely that the N-terminal gamma ANP fragment is metabolized by the liver. In patients with heart disease, plasma gamma ANP-(1-25)-LI and alpha ANP-LI levels were higher in those with cardiac decompensation and were positively correlated with right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure, indicating cosecretion of the N-terminal gamma ANP fragment and alpha ANP in response to atrial stretch.(ABSTRACT TRUNCATED AT 400 WORDS)
A Novel Class of Orally Active Non-Peptide Bradykinin B2 Receptor Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-a]pyridine Moiety (1998)

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1, 2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50's of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant.
The Development of an Anisotropic Si Etch Process Selective to Ge x Si1 − x Underlayers (1994)

In this paper we present the development of a technique for anisotropically etching silicon on . Wet chemical etching exhibits a selectivity of nearly 40:1 but is completely isotropic and requires the use of a hard mask. The fluorine plasma process which has been reported in the literature as having high selectivity was nonreproducible as a result of significant polymeric deposition on the chamber surfaces. Furthermore the etch residue was not easily removed in an plasma and led to highly resistive contacts. Reactive ion etch processes using and were found to anisotropically etch the silicon layer, but had poor selectively to . By combining a reactive ion etch at 300 W forward power and 20 mTorr in , with a wet chemical dip, an adequate process for selectively patterning submicron features was obtained.
Preparation and Properties of a Therapeutic Inter-Alpha-Trypsin Inhibitor Concentrate from Human Plasma (1994)

Inter-α-trypsin inhibitor (ITI) is a serine protease inhibitor found in human plasma. Its antiprotease activity is due to bikunin which is effective in various types of experimental shock and pancreatitis. Therefore ITI, which releases bikunin by proteolytic cleavage, could be of therapeutic interest. A method for the large- scale isolation of ITI from human plasma is described. ITI was purified from the prothrombin complex concentrate (PCC) by diethylaminoethyl-Sepharose fast- flow chromatography followed by a chromatographic step on immobilized heparin designed to remove C4, factor X and protein C. With this procedure, which was performed under mild conditions, a homogeneous preparation of native ITI was obtained, as demonstrated by electrophoretic and chromatographic analyses. ITI maintained its biological activity, as exhibited by its specific antitryptic activity of 420±65 IU/g. In order to decrease or eliminate the risk of transmission of viral disease due to lipid-enveloped viruses, the process incorporated a solvent- detergent treatment. Animal studies on the final product revealed no adverse side-effects in terms of toxicity, thrombogenicity or hypotension. This preparation appears suitable for therapeutic evaluation in animal experimental models.
Biomarkers for Diagnosis and Monitoring of Celiac Disease (2013)

Celiac disease (CD) is an autoimmune disorder, which damages the small intestine and is caused by ingestion of gluten in genetically susceptible individuals. The only known effective treatment is a lifelong gluten-free diet. Genetic risk factors have been identified and nearly all patients are HLA-DQ2 and/or HLA-DQ8 positive. Specific autoantibodies, IgA antitissue transglutaminase-2, antiendomysium, and antideaminated forms of gliadin peptide antibodies, are widely used as diagnostic aids in celiac patients. However, the discovery of new biomarkers may help in the diagnosis and follow-up of the disease. Recently, the molecule REG Iα, involved in tissue regeneration, has been proposed as a new biomarker of CD. REG Iα expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after gluten-free diet. In this article we review the main biomarkers for diagnosis and monitoring of CD, focusing on the immune response-related mechanisms.
THE CENTRAL EFFECTORS OF CELL DEATH IN THE IMMUNE SYSTEM (1999)

The immune system relies on cell death to maintain lymphoid homeostasis and avoid disease. Recent evidence has indicated that the caspase family of cysteine proteases is a central effector in apoptotic cell death and is absolutely responsible for many of the morphological features of apoptosis. Cell death, however, can occur through caspase-independent and caspase-dependent pathways. In the case of cells that are irreversibly neglected or damaged, death occurs even in the absence of caspase activity. In contrast, healthy cells require caspase activation to undergo cell death induced by surface receptors. This review summarizes the current understanding of these two pathways of cell death in the immune system.
Cell docking inside microwells within reversibly sealed microfluidic channels for fabricating multiphenotype cell arrays (2005)

We present a soft lithographic method to fabricate multiphenotype cell arrays by capturing cells within an array of reversibly sealed microfluidic channels. The technique uses reversible sealing of elastomeric polydimethylsiloxane (PDMS) molds on surfaces to sequentially deliver various fluids or cells onto specific locations on a substrate. Microwells on the substrate were used to capture and immobilize cells within low shear stress regions inside channels. By using an array of channels it was possible to deposit multiple cell types, such as hepatocytes, fibroblasts, and embryonic stem cells, on the substrates. Upon formation of the cell arrays on the substrate, the PDMS mold could be removed, generating a multiphenotype array of cells. In addition, the orthogonal alignment and subsequent attachment of a secondary array of channels on the patterned substrates could be used to deliver fluids to the patterned cells. The ability to position many cell types on particular regions within a two dimensional substrate could potentially lead to improved high-throughput methods applicable to drug screening and tissue engineering.
Fault detection with multiple observers (1992)

The authors propose to use a set of independent observers to detect faults in communication systems that are modeled by finite-state machines. An algorithm for constructing these observers and a fast real-time fault detection mechanism used by each observer are given. Since these observers run in parallel and independently, one immediate benefit is that of graceful degradation; one failed observer will not cause collapse of the fault management system. In addition, each observer has a simpler structure than the original system and can be operated at higher speed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation (2002)

Although the beneficial effects of ventricular rate (VR) slowing during atrial fibrillation (AF) are axiomatic, the precise relationship between VR and hemodynamics has not been determined. We hypothesized that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) by varying the nerve stimulation intensity could achieve precise graded slowing and permit evaluation of an optimal VR during AF. The aims of the present study were the following: 1) to develop a method for computerized vagally controlled VR slowing during AF, 2) to determine the hemodynamic changes at each level of VR slowing, and 3) to establish the optimal anterograde VR during AF. AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 14 dogs. Four target average VR levels, corresponding to 75%, 100%, 125%, and 150% of the sinus cycle length (SCL), were achieved by computer feedback algorithm. VR slowing resulted in improved hemodynamics and polynomial fit analysis found an optimum for the cardiac output at VR slowing of 87% SCL. We conclude that this novel method can be used to maintain slow anterograde conduction with best hemodynamics during AF.
Estrogen Receptor-β: Recent Lessons from in Vivo Studies (2006)

The unexpected discovery of a second form of the estrogen receptor (ER), designated ERbeta, surprised and energized the field of estrogen research. In the 9 yr since its identification, the remarkable efforts from academic and industrial scientists of many disciplines have made significant progress in elucidating its biology. A powerful battery of tools, including knockout mice as well as a panel of receptor-selective agonists, has allowed an investigation into the role of ERbeta. To date, in vivo efficacy studies are limited to rodents. Current data indicate that ERbeta plays a minor role in mediating estrogen action in the uterus, on the hypothalamus/pituitary, the skeleton, and other classic estrogen target tissues. However, a clear role for ERbeta has been established in the ovary, cardiovascular system, and brain as well as in several animal models of inflammation including arthritis, endometriosis, inflammatory bowel disease, and sepsis. The next phase of research will focus on elucidating, at a molecular level, how ERbeta exerts these diverse effects and exploring the clinical utility of ERbeta-selective agonists.
Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells (2016)

Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy.
Diurnal cycle of emission of induced volatile terpenoids by herbivore-injured cotton plant. (1994)

Cotton plants attacked by herbivorous insect pests emit relatively large amounts of characteristic volatile terpenoids that have been implicated in the attraction of natural enemies of the herbivores. However, the composition of the blend of volatile terpenes released by the plants varies remarkably throughout the photoperiod. Some components are emitted in at least 10-fold greater quantities during the photophase than during the scotophase, whereas others are released continuously, without conforming to a pattern, during the entire time that the plants are under herbivore attack. The diurnal pattern of emission of volatile terpenoids was determined by collecting and analyzing the volatile compounds emitted by cotton plants subjected to feeding damage by beet armyworm larvae in situ. The damage was allowed to proceed for 3 days, and volatile emission was monitored continuously. During early stages of damage high levels of lipoxygenase-derived volatile compounds [e.g., (Z)-3-hexenal, (Z)-3-hexenyl acetate] and several terpene hydrocarbons [e.g., alpha-pinene, caryophyllene] were emitted. As damage proceeded, high levels of other terpenes, all acyclic [e.g., (E)-beta-ocimene, (E)-beta-farnesene], were emitted in a pronounced diurnal fashion; maximal emissions occurred in the afternoon. These acyclic terpenes followed this diurnal pattern of emission, even after removal of the caterpillars, although emission was in somewhat smaller amounts. In contrast, the emission of cyclic terpenes almost ceased after the caterpillars were removed.
Immunologic and clinical modifications following low-dose subcutaneous administration of rIL-2 in non-Hodgkin's lymphoma patients after autologous bone marrow transplantation. (1996)

In order to induce a therapeutic immunomodulatory activity, 11 patients with high-grade non-Hodgkin's lymphoma (HG-NHL) at a median of 42 days after autologous bone marrow transplantation (ABMT) received recombinant interleukin-2 (rIL-2) subcutaneously at a dose of 2 international megaunits (IMU)/m2 every other day for 2 weeks and then 3 IMU/m2 twice a week for 1 year. Immunological studies, including T and natural killer (NK) cell subset assessment, together with functional assay, such as NK and CD16-mediated cytotoxic activities, were performed before therapy, after 2 weeks and then monthly. Phenotypic analyses showed a significant and persistant (P = 0.001) increase in the proportion and absolute number of total lymphocytes and, particularly of both CD16 and CD56 NK cells, from pre-treatment values of 14 and 18% to 30 and 38% respectively, recorded after 6 months of therapy. No changes were observed in CD25 (p55)-positive cells, while a significant increase from 13 to 33% (after 6 months) was observed in CD122-positive cells. Furthermore, rIL-2 administration led to an enhancement of NK activity even at the lowest effector:target ratio and of CD16-mediated cytotoxic activity. Clinical tolerance was acceptable with moderate fever and fluid retention observed only at the onset of rIL-2 treatment. None of the patients have progressed with a median follow-up of 22 months (range 10-42 months) after starting therapy. In addition, two patients with a residual disease after ABMT, one in the liver and the second in the lymph nodes, obtained a complete response after 10 and 7 months of rIL-2 therapy, respectively. These preliminary data suggest that the infusion of low-dose rIL-2 s.c. after ABMT is safe and well tolerated and can selectively increase the NK cell number and function. Additional patients are needed in order to assess the impact of these immunological changes on relapse-free survival after ABMT for HG-NHL.
Evidence for the involvement of a cytoplasmic factor in the aging of the yeast Saccharomyces cerevisiae (1989)

The life spans of individual Saccharomyces cerevisiae cells were determined microscopically by counting the number of buds produced by each cell to provide a measure of the number of cell generations (age) before death. As the cells aged, their generation times increased five- to sixfold. The generation times of daughter cells were virtually identical to those of their mothers throughout the life spans of the mothers. However, within two to three cell divisions after the daughters were detached from their mothers by micromanipulation, their generation times reverted to that characteristic of their own age. Recovery from the mother cell effect was also observed when the daughters were left attached to their mothers. The results suggest that senescence, as manifested by the increase in generation time, is a phenotypically dominant feature in yeast cells and that it is determined by a diffusible cytoplasmic factor(s) that undergoes turnover. This factor(s) appeared to be transmitted by a cell not only to its daughter, but also indirectly to its granddaughter. In separate studies, it was determined that the induced deposition of chitin, the major component of the bud scar, in the yeast cell wall had no appreciable effect on life span. We raise the possibility that the cytoplasmic factor(s) that appears to mediate the "senescent phenotype" is a major determinant of yeast life span. This factor(s) may be the product of age-specific gene expression.
Regulated expression of nuclear genes by T3 RNA polymerase and lac repressor, using recombinant vaccinia virus vectors (1990)

Recombinant vaccinia viruses that express the bacteriophage T3 RNA polymerase (VV-T3pol) or the Escherichia coli lac repressor (VV-lacI) under control of the early-late vaccinia promoter P7.5 were constructed. To determine whether phage polymerase and lac repressor can function in the nucleus of mammalian cells, the bacterial chloramphenicol acetyltransferase (CAT) gene was cloned downstream of a T3 promoter (PT3-CAT) or downstream of a T3 promoter-lac operator fusion element (PT3Olac-CAT), and these reporter gene cassettes were introduced stably into NIH 3T3 or Ltk- cells. Infection of 3T3/PT3-CAT or Ltk-/PT3-CAT cells by VV-T3pol led to rapid expression of CAT (greater than 20 ng of CAT protein per 10(6) cells). The presence of hydroxyurea (which blocks virus DNA replication) did not prevent CAT production. When 3T3/PT3Olac-CAT cells were infected with both VV-T3pol and VV-lacI (multiplicities of infection of 2.5 and 10, respectively), greater than 30-fold repression of CAT gene activity by lac repressor was observed. This could be reversed to unrepressed levels by the presence of 10 mM o-nitrophenyl-beta-D-galactoside (IPTG) in the medium. Regulated expression of the target gene was observed with cell lines that had been maintained for over 1 year (greater than 50 passages in culture), and Southern blot analysis revealed the presence of the CAT gene only in the nuclear fraction in these cells, demonstrating the stability of the target gene. These results indicate that vaccinia virus-encoded proteins can function in the mammalian nucleus and provide the basis for a genetic system in which essential vaccinia virus genes, placed in the chromosome of a cell, can be used to complement defective virus particles. This approach may prove useful for other virus systems.
Accessory and stimulating properties of dendritic cells and macrophages isolated from various rat tissues (1982)

Single cell suspensions of rat lymphoid and nonlymphoid tissues were fractionated on discontinuous gradients of bovine serum albumin into high density and low density subfractions. In general, accessory activity required for responses of periodate-treated T lymphocytes was recovered only in a low density population containing a small percent of the total fractionated cells from lymph nodes, spleen, liver, skin, and peritoneal exudates. Further purification always led to an increase of both accessory activity and number of dendritic cells present in nonrosetting and nonadherent populations. After purification, a high recovery of the total accessory activity was found in fractions that contained a high percentage of dendritic cells resulting in a more than 1,000-fold enrichment in accessory activity per cell. No other fraction obtained during the purification contained significant accessory activity. In all cases, macrophage-enriched populations lacked accessory cell activity. With the exception of peritoneal exudate cell preparations, which contained an inhibitory cell, the level of accessory activity in a given population was always found to be a function of the number of dendritic cells present. Dendritic cells from all sources were nonadherent, nonphagocytic, radio- resistant, and nonspecific esterase negative. They expressed Ia antigens and lacked Fc receptors. Both epidermal and lymph node dendritic cells contain Birbeck granules, subcellular structures previously described only for Langerhans cells. Accessory activity requires viable dendritic cells but is unaffected by 1,000 rad of gamma-irradiation. However, ultraviolet irradiation abolished the activity of accessory cells. The cells that responded to periodate were IgG-negative T cells, whereas IgG-positive B cells could not be stimulated under the same conditions. Only periodate-treated T cells and dendritic cells were needed for responses to occur; removal of virtually all macrophages from these purified preparations had no effect. Dendritic cells were also required as stimulators in mixed leukocyte cultures, whereas macrophages, even though Ia positive, were inert.