gebhart/patrepeval huggingface dataset:
eIF2B Mechanisms of Action and Regulation: A Thermodynamic View (2018)

Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor of the GTPase eIF2, which brings the initiator Met-tRNA<sub>i</sub> to the ribosome in the form of the eIF2-GTP·Met-tRNA<sub>i</sub> ternary complex (TC). The activity of eIF2B is inhibited by phosphorylation of its substrate eIF2 by several stress-induced kinases, which triggers the integrated stress response (ISR). The ISR plays a central role in maintaining homeostasis in the cell under various stress conditions, and its dysregulation is a causative factor in the pathology of a number of neurodegenerative disorders. Over the past three decades, virtually every aspect of eIF2B function has been the subject of uncertainty or controversy: from the catalytic mechanism of nucleotide exchange, to whether eIF2B only catalyzes nucleotide exchange on eIF2 or also promotes binding of Met-tRNA<sub>i</sub> to eIF2-GTP to form the TC. Here, we provide the first complete thermodynamic analysis of the process of recycling of eIF2-GDP to the TC. The available evidence leads to the conclusion that eIF2 is channeled from the ribosome (as an eIF5·eIF2-GDP complex) to eIF2B, converted by eIF2B to the TC, which is then channeled back to eIF5 and the ribosome. The system has evolved to be regulated by multiple factors, including post-translational modifications of eIF2, eIF2B, and eIF5, as well as directly by the energy balance in the cell, through the GTP:GDP ratio.
Synthesis and bioactivity of novel triazolo [1,5‐a]pyrimidine derivatives[3] (2001)

Abstract In an attempt to discover novel compounds with high herbicidal activity and low toxicity, a series of novel 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives, α‐(5,7‐dimethyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐2‐thio)acetamides 3 and α‐(5,7‐dimethyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐2‐sul‐fonyl)acetamides 4 , have been designed and synthesized by a three‐step synthetic route. The structures of all compounds prepared were confirmed by elemental analyses and by 1 H NMR and mass spectroscopy. The results of preliminary bioassay indicate that the title compounds possess good herbicidal activity against rape (Brassica campestris L.) and barnyardgrass (Echinochloca crusgalli L.) © 2001 John Wiley &amp; Sons, Inc. Heteroatom Chem 12:491–496, 2001
Platelet‐Derived Growth Factor Enhancement of a Mineral‐Collagen Bone Substitute (2000)

These results suggest that PDGF-BB is rapidly adsorbed then slowly released from the anorganic bovine bone-collagen matrix. PDGF-BB adsorbed to this material is able to stimulate proliferation of the attached osteoblastic cells. These data suggest that it may be clinically feasible to adsorb PDGF to this bone-collagen matrix and that this combination of bone growth factor and mineral-collagen matrix has the potential for clinical applications.
Oral N-acetyl-l-cysteine is a safe and effective precursor of cysteine1 (2007)

Relative bioavailability and toxicity of N-acetyl-l-Cys (NAC) were evaluated in 9-d chick growth assays. The bioavailability of NAC relative to Cys was determined by feeding young chicks a highly purified crystalline AA diet singly deficient in Cys. Bio-availability estimates were obtained using standard slope-ratio methodology. N-Acetyl-l-cysteine was shown to be as effective as Cys in supporting chick growth, and was assigned a relative bioavailability value of 100%. To assess toxicity, a nutritionally adequate corn-soybean meal diet was supplemented with graded concentrations of NAC (isomolar to 10, 20, 30, or 40 g/kg of Cys, as-fed). When NAC supplied 10 or 20 g/kg of Cys, chick growth performance was unaffected, but NAC supplying 30 or 40 g/kg of Cys reduced (P < 0.05) BW gain by 13 and 34%, respectively, relative to the unsupplemented control diet. Only plasma-free NAC was substantially increased (P < 0.05) because of excess dietary NAC; plasma-free Cys was unaltered. We concluded that dietary NAC is efficacious in supplying Cys in support of chick growth, and only large excesses of NAC are growth depressing. Hence, the human clinical benefits of oral NAC likely result from its ability to deliver Cys safely and effectively to the portal circulation.
Computer eye looks at human eye (1984)

A television ophthalmoscope (TVO) developed at the University of Illinois at Chicago combines low-light-level television camera and digital image processor to acquire and analyze images of the retina and chorold, one of the few areas of the body where the circulatory system can be observed in detail without surgery. So Far the TVO has been used in two-wavelength oxlmetry to measure oxygen saturation in the blood—a measure useful in diagnosing and treating diabetes, with potential for better management of sickle-cell anemia, hypertension and other systemic diseases. The TVO image processor also analyzes multispectral reflectance images which have been used, for example, to calculate and display difference images of visual pigment density, related to night blindness and other inherited ele disorders. In addition, the use of the TVO in quantitative angiography has contributed to understanding of the dynamics of retinal/choroidal blood flow.Experimental studies are presented that demonstrate two complementary techniques for the extraction of hemodynamic parameters from TVO-derived anglographic data. In particular both the frequency domain technique and the time domain technique presented are capable of obtaining retinal circulation time (RCT) estimates from nonuniformly sampled and noisy dye dilution curves. Both methods use identical input (artery dye dilution curve) and response (vein dye dilution curve). The frequency domain technique uses this information for obtaining transfer function estimates of the retinal capillary bed. These estimates are then used to obtain minimum mean square error values of parameters in a model of the capillary bed. The model was chosen so as to account for both the tracer transit time, which is the time the response is delayed relative to the input, and tracer dispersion, which is the extent to which the response pulse is spread out relative to the input pulse. This spreading effect is determined by the variation in capillary lengths within a capillary bed and by various types of mixing.
Can't Get Any Help? New Approaches for Adoptive Immunotherapy of Cancer (2001)

Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
Suppressive Influences in the Immune Response to Cancer (2008)

Although much evidence has been gathered demonstrating that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells do evade immune surveillance in most cases. Considering that anticancer active specific immunotherapy seems to have reached a plateau of results and that currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted.
A reconfigurable leaky-wave/patch microstrip aperture for phased-array applications (2002)

A novel reconfigurable leaky-wave/patch microstrip aperture is introduced and characterized. The structure consists of a long leaky-wave microstrip antenna that has been segmented into several smaller patch antennas. The multimode structure can be reconfigured into a patch antenna anywhere along the aperture of the leaky-wave antenna with two degrees of freedom. p-i-n-diode switches are utilized to switch between the different aperture configurations. The structure's unique field profile is utilized to minimize insertion loss in the leaky-wave mode and also to maximize isolation between the different aperture ports. Radiation patterns demonstrate excellent radiation characteristics consistent with standard leaky-wave and patch-antenna patterns. The reconfigurable leaky-wave/patch concept is applied to realize some unique multimode array configurations offering wide scan coverage and enhanced flexibility over traditional phased-array systems.
Influence of Glucocorticoids on Glucagon Secretion and Plasma Amino Acid Concentrations in Man (1973)

Plasma concentrations of glucagon, insulin, glucose, and individual plasma amino acids were measured in normal nonobese and obese subjects before and after 3 days of dexamethasone treatment (2 mg/day) and in patients with Cushing's syndrome. The subjects were studied in the basal postabsorptive state and following the infusion of alanine (0.15 g/kg) or ingestion of a protein meal. In nonobese subjects dexamethasone treatment resulted in a 55% increment in basal glucagon levels and in a 60-100% increase in the maximal glucagon response to alanine infusion or protein ingestion. In obese subjects, basal glucagon rose by 110% following dexamethasone, while the response to alanine increased fourfold. In patients with Cushing's syndrome basal glucagon levels were 100% higher and the glucagon response to alanine infusion was 170% greater than in normal controls.Dexamethasone treatment in normal subjects resulted in a 40% rise in plasma alanine concentration which was directly proportional to the rise in basal glucagon. The remaining 14 amino acids were unchanged. In the patients with Cushing's syndrome alanine levels were 40% higher than in normal controls and were directly proportional to basal glucagon concentrations. No other plasma amino acids were significantly altered in the group with Cushing's syndrome. It is concluded that (a) glucocorticoids increase plasma glucagon concentration in the basal state and in response to protein ingestion or aminogenic stimulation; (b) this effect of glucocorticoids occurs in the face of obesity and persists in chronic hypercorticism; (c) hyperalaninemia is a characteristic of acute and chronic glucocorticoid excess, and may in turn contribute to steroid-induced hyperglucagonemia; and (d) increased alpha cell secretion may be a contributory factor in the gluconeogenic and diabetogenic effects of glucocorticoids.
Role of the monoclonal chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome (2006)

Acquired Fanconi syndrome (FS) is a complication of monoclonal gammopathies featuring a generalized dysfunction of the proximal tubule of the kidney, due to the storage within proximal tubular cells of a monoclonal immunoglobulin light chain. We engineered transgenic mice in which the endogenous mouse Jkappa cluster was replaced by a human VkappaJkappa rearranged gene cloned from a patient with smoldering myeloma-associated FS. The V region belonged to the VkappaI subgroup and was related to the O2-O12 germ-line gene, a V segment previously found associated with FS and light-chain crystallization in several patients with myeloma. Association of the human VkappaI domain with a mouse kappa constant domain in transgenic animals yielded a nephrotoxicity pattern similar to that observed in patients, strongly suggesting that the whole pathogenic effect of FS light chains can be ascribed to a peculiar structure of the V domain. Morphologic alterations of the kidney tubular cells, which contained rhomboid-shape crystals, were observed in mice, together with alterations of the proximal tubule reabsorption function. Moreover, the number of renal crystalline inclusions was dramatically reduced after conditional deletion of the human VkappaI transgene, showing that proximal tubular lesions are reversible upon suppression of the nephrotoxic light chain secretion.
Fat-suppressed three-dimensional spoiled gradient-recalled MR imaging: assessment of articular and physeal hyaline cartilage. (1997)

Fat-suppressed 3D SPGR imaging is a widely available technique that allows accurate evaluation of hyaline cartilage. The use of this sequence is helpful in confirming suggestive findings on standard MR imaging sequences and often allows diagnosis of conditions that otherwise would have gone undetected.
Monoclonal antibodies: Principles and practice : production and application of monoclonal antibodies in cell biology, biochemistry, and immunology (1983)

Introduction. The Antibody Response. Cellular Basis of the Immune System. Nature of Antigens. Antibody Structure and Function. Genetics of Antibodies. Introduction to Monoclonal Antibodies. Production of Monoclonal Antibodies. Purification. Fragmentation and Isotopic Labeling of Monoclonal Antibodies. Analysis of Antigens Recognized By Monoclonal Antibodies. Affinity Chromatography Immunofluorescence. Immunohistology. Construction, Screening and Expression of Recombinant Antibodies. Generation of Conventional Antibodies.
3-Hydroxypyrroles. II. The reaction of 4,5-unsubstituted alkyl 3-hydroxypyrrole-2-carboxylates with some electrophiles. (1978)

The reaction of alkyl 3-hydroxypyrrole-2-carboxylates (1) with some electrophiles was investigated. The alkylation of 1c occurred at the O and C-2 position as in the case of usual β-keto esters. An N-substituted 3-hydroxypyrrole-2-carboxylate (1e) reacted at the 2-position upon the Michael reaction. In addition to the C-2 adduct (9), an unexpected 2, 2-bis-adduct (10) was concurrently obtained possibly via the ketonic cleavage of the mono-adduct (9) followed by the second addition of acrylate. The N-unsubstituted one (1b) gave a mono-adduct at C-2 (12) and a bis-adduct at C-2 and N (13). Upon bromination, 1c reacted at the 4-and 5-position, not at the 2-position ; namely 1c reacted with bromine as an enamine or a pyrrole, and not as a β-keto ester. The Mannich reaction occurred rapidly and selectively at the 4-position, and the 4-bromo derivative (15) reacted preferentially at the 5-position. In the cyanation of the quarternary salts of the Mannich bases, a dimer (23), a trimer (24) and a dicyano compound (26) were obtained in addition to the expected cyanides (22, 25).
A Digital Controlled PV-Inverter With Grid Impedance Estimation for ENS Detection (2005)

The steady increase in photovoltaic (PV) installations calls for new and better control methods in respect to the utility grid connection. Limiting the harmonic distortion is essential to the power quality, but other requirements also contribute to a more safe grid-operation, especially in dispersed power generation networks. For instance, the knowledge of the utility impedance at the fundamental frequency can be used to detect a utility failure. A PV-inverter with this feature can anticipate a possible network problem and decouple it in time. This paper describes the digital implementation of a PV-inverter with different advanced, robust control strategies and an embedded online technique to determine the utility grid impedance. By injecting an interharmonic current and measuring the voltage response it is possible to estimate the grid impedance at the fundamental frequency. The presented technique, which is implemented with the existing sensors and the CPU of the PV-inverter, provides a fast and low cost approach for online impedance measurement, which may be used for detection of islanding operation. Practical tests on an existing PV-inverter validate the control methods, the impedance measurement, and the islanding detection.
Advances in plasmid gene delivery and expression in skeletal muscle. (2000)

One of the most striking recent advances for plasmid delivery in vivo has been that of electropermeabilization, commonly referred to as electroporation. This physical process exposes a muscle tissue to a brief, high intensity electric field that induces temporary and reversible breakdown of the plasma membrane. During the period of membrane destabilization, a variety of molecules, including plasmids, gain intracellular access. Electroporation has been shown to improve the efficiency of plasmid gene delivery to skeletal muscle of small animals by as much as two-orders of magnitude to levels comparable to that of adenoviral gene delivery. This technology will allow the muscle to be used as a bioreactor for the secretion of therapeutic proteins into the circulation. This method of gene delivery, which is simple, efficient and reproducible, has become valuable for basic research, with great potential for gene therapy and DNA vaccination. Moreover, significant progress has been made using a variety of molecular designs to achieve regulation of gene expression by low molecular weight drugs. The enhanced efficiency of plasmid delivery by electroporation and the resultant durability of transgene expression, combined with the effectiveness of drug-dependent transgene regulation systems, provide a powerful set of tools that will be broadly applicable to the development of plasmid-based gene therapies for the treatment of human disease.
Herpes simplex virus type 1 Fc receptor protects infected cells from antibody-dependent cellular cytotoxicity (1991)

Recent studies indicate that the herpes simplex virus type 1 (HSV-1) Fc receptor (FcR) can bind antiviral immunoglobulin G by participating in antibody bipolar bridging. This occurs when the Fab domain of an immunoglobulin G molecule binds to its antigenic target and the Fc domain binds to the HSV-1 FcR. In experiments comparing cells infected with wild-type HSV-1 (NS) and cells infected with an FcR-deficient mutant (ENS), we demonstrate that participation of the HSV-1 FcR in antibody bipolar bridging reduces the effectiveness of antibody-dependent cellular cytotoxicity.
Two-color holographic recording scheme allowing nonvolatile reading in Mn:YAlO_3 (2001)

We propose and experimentally realize the recording of two-color holographic gratings in Mn:YAlO(3), a potential material for holographic data storage. This type of recording allows for nonvolatile retrieval of recorded information at the recording wavelength. We demonstrate two-color recording and readout of a 256 x 256 pixel page using red and green laser beams with a bit error rate of 6 x 10(-7).
MON-089 Discovery and Identification of Late Stage Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists for the Treatment of Hyperinsulinemic Hypoglycemia (2020)

Abstract Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1:2500 to 1:50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, a near-total pancreatectomy may be required, but hypoglycemia often persists. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. The injectable peptide drugs octreotide and lanreotide are potent sst2 agonists used to treat CHI, but in addition to suppressing insulin, the sst2 activity of these peptides may also inhibit glucagon secretion, potentially reducing effectiveness and compromising a key defense against hypoglycemia. Glucagon secretion from α-cells is inhibited through activation of sst2 receptors, while insulin secretion from β-cells is inhibited through activation of sst2 and sst5. We therefore hypothesize that agonists selectively targeting sst5 and lacking sst2 activity will offer an improved efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry and pharmacology, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. Insulin secretion from isolated human and rat islets was suppressed upon exposure to sst5 agonists. Potent and selective sst5 agonists were then evaluated in a number acute and repeat dose in vivo models (e.g., oGTT, fed/fasted conditions, sulfonylurea-induced hypoglycemia) to assess physiological effects and to gain mechanistic insights. As predicted by the in vitro pharmacology, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels in each model, while having minimal effects on glucagon secretion. Leading sst5 agonists were also evaluated for drug like characteristics, including stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicity studies to determine the molecule most suitable for evaluation in human clinical trials.
Neuroprotection (2007)

The ability of pharmacological agents to limit secondary biochemical damage and cell death has been well established in numerous animal models of stroke, head injury, and spinal cord injury, yet the results of such neuroprotective treatment strategies in human injury have been disappointing. A number of conceptual and methodological issues have undoubtedly contributed to the difficulties in translating the experimental results to the clinic. Most recently, different experimental approaches and altered clinical trial methodologies have provided renewed, albeit cautious, optimism regarding future clinical trials of neuroprotective agents. Herein, we reviewed both the critical problems and potential solutions, emphasizing recent experimental and clinical work.
Narrow Channel Forced Air Heat Sink (1984)

The heat transfer between the coolant anti the heat sink contributes a significant fraction of the thermal resistance of a package. It has been widely recognized that the heat transfer can be increased by increasing the area of the heat sink in contact with the coolant, and therefore the use of fins is common. However it has not been generally recognized that for laminar flow in confined channels, the heat transfer coefficient is inversely proportional to the width of the channel. Narrow channel forced air heat sinks have been designed, built, and tested. Three different channel widths, 5, 10, and 25 mils, were investigated. The design of the sinks permit integrated circuits (IC's) on 1/2 in centers and printed circuit (PC) boards on I in centers. The measured values of individual heat sinks with 30 I/min air flow are 5.5, 3.7, and 3.4°C/W for 25,10, and 5 mil channel widths, respectively. These values are in good agreement with calculated values. A 16 chip package with chips on 1/2 in centers was assembled utilizing 10 mil channel width heat sinks. A plenum fitted over the sinks supplied air to each of the sinks from a single source. The measured values of thermal resistance of the four center dies were between 5.3 and 5.9°C/W. If the chips are mounted directly on the sink instead of on the alumina substrate, the thermal resistance would be reduced by about 2°C/W.