gebhart/patrepeval huggingface dataset:
Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP (2013)

A series of novel, potent antagonists of the inhibitor of apoptosis proteins (IAPs) were synthesized in a highly convergent and rapid fashion (≤6 steps) using the Ugi four-component reaction as the key step, thus enabling rapid optimization of binding potency. These IAP antagonists compete with caspases 3, 7, and 9 for inhibition by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding constants) to several crucial members of the IAP family of cancer pro-survival proteins to promote apoptosis, with a particularly unique selectivity for melanoma IAP (ML-IAP). Experiments in cell culture revealed powerful cancer cell growth inhibitory activity in multiple (breast, ovarian, and prostate) cell lines with single agent toxicity at low nanomolar levels against SKOV-3 human ovarian carcinoma cells. Administration of the compounds to human foreskin fibroblast cells revealed no general toxicity to normal cells. Furthermore, computational modeling was performed, revealing key contacts between the IAP proteins and antagonists, suggesting a structural basis for the observed potency.
Association between Hypothyroidism and Small Intestinal Bacterial Overgrowth (2007)

The history of overt hypothyroidism is associated with bacterial overgrowth development. Excess bacteria could influence clinical gastrointestinal manifestations. Bacterial overgrowth decontamination is associated with improved gastrointestinal symptoms. However, fermenting carbohydrate luminal bacteria do not interfere with thyroid hormone levels.
A Fluorescence Resonance Energy Transfer-based Sensor Indicates that Receptor Access to a G Protein Is Unrestricted in a Living Mammalian Cell (2004)

Fluorescence recovery after photobleaching of muscarinic receptors and G protein subunits tagged with cyan or yellow fluorescent protein showed that receptors and G proteins were mobile and not immobilized on the cell membrane. The cyan fluorescent protein-tagged Galpha and yellow fluorescent protein-tagged Gbeta subunits were used to develop sensors that coupled selectively with the M2 and M3 muscarinic receptors. In living Chinese hamster ovary cells, imaging showed that sensors emitted a fluorescence resonance energy transfer signal that was abrogated on receptor activation. When sequentially activated with highly expressed muscarinic receptors and endogenous receptors expressed at low levels, sensor molecules were sensitive to the sequence of activation and the receptor numbers. The results distinguish between models proposing that receptor and G protein types interact freely with each other on the cell membrane or that they function as mutually exclusive multimolecular complexes by providing direct support for the former model in these cells.
Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation (2002)

Glycogen synthase kinase 3 (GSK-3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. Two forms of the enzyme, GSK-3alpha and GSK-3beta, have been previously identified. Small molecules inhibitors of GSK-3 may, therefore, have several therapeutic uses, including the treatment of neurodegenerative diseases, diabetes type II, bipolar disorders, stroke, cancer, and chronic inflammatory disease. As there is lot of recent literature dealing with the involvement of GSK-3 in the molecular pathways of different diseases, this review is mainly focused on the new GSK-3 inhibitors discovered or specifically developed for this enzyme, their chemical structure, synthesis, and structure-activity relationships, with the aim to provide some clues for the future optimization of these promising drugs.
Future indications for sacral nerve stimulation (2011)

Good quality prospective, cross-over studies are required to determine the true benefits of SNS. Further research into patient selection, operative technique and stimulation parameters for existing indications will ensure a place for SNS in the future treatment algorithm of functional pelvic floor disorders.
Textbook of Receptor Pharmacology (2002)

The bestselling first edition of Textbook of Receptor Pharmacology originated from a renowned course in receptor pharmacology taught at the University College of London for the past three decades. Its innovative format united four major approaches to the study of receptors: molecular biology, quantitative functional studies of agonists and antagoni
Amino acids 367-376 of the Gs alpha subunit induce membrane association when fused to soluble amino-terminal deleted Gi1 alpha subunit. (1991)

Signal transduction GTP-binding proteins are tightly associated with plasma membrane. In the resting state, the anchorage of the alpha subunit could be indirect by means of the other beta gamma subunits or polydisperse multimers. In the activated state, although the alpha subunit is dissociated from other subunits, it is not released from the membrane and therefore is likely to contain information necessary to remain associated with the plasma membrane. Previous proteolytic experiments suggested that, in contrast to other G proteins alpha subunits, the C-terminal domain of Gs alpha (the G protein involved in adenylate cyclase stimulation) is essential for membrane association of the activated form. To better define the crucial residues involved in membrane attachment, we constructed chimeras between a soluble core and various parts of the Gs alpha C-terminal domain. We first deleted codons 2-6 of Gi1 alpha (the inhibitory G protein of the i1 subtype) to generate a soluble GTP-binding protein, delta N-Gi1 alpha. We then replaced the last 14 C-terminal codons of delta N-Gi1 alpha by different domains of the Gs alpha C terminus and looked for the membrane association of chimeric proteins after in vitro transcription, in vitro translation, and interaction with S49 cyc- membranes (obtained from a mutant cell line that does not express Gs alpha). Our results showed that addition of amino acids 367-376 of Gs alpha is sufficient to promote membrane association of the soluble N-terminal deleted Gi1 alpha.
Sound System (2003)

At the heart of reggae lies the sound system. In the early days of the phenomenon, during the late 1940s and early 1950s in Jamaica, a sound system was scarcely more than a turntable, an amplifier and a pair of speakers, playing the latest in US rhythm and blues (R&B) (sprinkled with the odd swing a
Epidemiology of Moderate-to-Severe Plaque Psoriasis in a Canadian Surveyed Population (2010)

the findings are consistent with a substantial burden attributed to moderate-to-severe plaque psoriasis in a Canadian population.
Head and Spinal Trajectories in Children and Adults Exposed to Low Speed Frontal Acceleration (2009)

Head injuries are the most common injuries sustained by children in motor vehicle crashes. Prevention of these injuries through advances in vehicles and restraint systems requires a biofidelic anthropometric test device (ATD). Pediatric ATDs are primarily developed from scaling down adult volunteer and cadaver impact test data. Limited experimental data exist on pediatric head and neck kinematics in order to evaluate the biofidelity of the ATDs. The aim of the current study was to evaluate the head and spinal kinematics of pediatric and adult volunteers in response to a dynamic low-speed frontal sled test. Low speed volunteer testing of five male subjects in each of two specific age groups (9- 12, and 18-30 years) were performed using a pneumatically actuated - hydraulically controlled sled. Safe limits were established from measurement of bumper car accelerations at an amusement park ride (4.9 g, 55.7 msec rise time, 110 msec duration), which we believed to be sub-injurious to the adult and child amusement park population. The bumper car environment was subsequently recreated in the laboratory, by developing a low-speed hydropneumatic sled. As an added measure of safety, the average maximum cart acceleration was 3.59 g for children and 3.78 g for adults, thus producing occupant loads that are approximately 25% less than the bumper car amusement park ride. Spherical reflective markers were placed on the head, neck, torso, upper and lower extremities and tracked using a 3D motion analysis system. An angular rate sensor was mounted to a bite plate of an athletic mouth guard to measure the head rotational velocity. Electromyography sensors were attached to key muscle groups to measure the muscle response of the subjects to the loading environment. Each subject was subjected to six sled runs. Head and neck trajectories were compared between the adult and pediatric subjects. In addition, the effect of habituation on kinematic response was examined by comparing within subject changes in kinematics throughout the series of six sled runs. The full text of this paper may be found at: http://www-nrd.nhtsa.dot.gov/pdf/esv/esv21/09-0263.pdf For the covering abstract see ITRD E145407.
Variation in Transistor Performance and Leakage in Nanometer-Scale Technologies (2008)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> Variation in transistor characteristics is increasing as CMOS transistors are scaled to nanometer feature sizes. This increase in transistor variability poses a serious challenge to the cost-effective utilization of scaled technologies. Meeting this challenge requires comprehensive and efficient approaches for variability characterization, minimization, and mitigation. This paper describes an efficient infrastructure for characterizing the various types of variation in transistor characteristics. A sample of results obtained from applying this infrastructure to a number of technologies at the 90-, 65-, and 45-nm nodes is presented. This paper then illustrates the impact of the observed variability on SRAM, analog and digital circuit blocks used in system-on-chip designs. Different approaches for minimizing transistor variation and mitigating its impact on product performance and yield are also described. </para>
Efficient waveform inversion and imaging: A strategy for selecting temporal frequencies (2003)

Abstract Prestack migration and/or inversion may be implemented in either the time or the frequency domain. In the frequency domain, it is possible to discretize the frequencies with a much larger sampling interval than that dictated by the sampling theorem and still obtain an imaging result that does not suffer from aliasing (wrap around) in the depth domain. The selection of input frequencies can be reduced when a range of offsets is available; this creates a redundancy of information in the wavenumber coverage of the target. In order to optimize the use of this information, we define a new discretization strategy that depends on the maximum effective offset present in the surface seismic survey: the larger the range of offsets, the fewer frequencies are required. The strategy, exact in a homogeneous 1D earth, selects frequencies by making use of the well-known effect of image stretch in normal-moveout (NMO) correction and in migration (usually considered detrimental for the imaging). The strategy is also useful in more general earth models: we apply it to the 2D Marmousi model and recover a continuous range of wavenumbers using only three input frequencies. The Marmousi inversion result accurately predicts all other data frequencies, demonstrating the redundancy of the data.
Breaking the N2 triple bond: insights into the nitrogenase mechanism (2006)

Nitrogenase is the metalloenzyme that performs biological nitrogen fixation by catalyzing the reduction of N2 to ammonia. Understanding how the nitrogenase active site metal cofactor (FeMo-cofactor) catalyzes the cleavage of the N2 triple bond has been the focus of intense study for more than 50 years. Goals have included the determination of where and how substrates interact with the FeMo-cofactor, and the nature of reaction intermediates along the reduction pathway. Progress has included the trapping of intermediates formed during turnover of non-physiological substrates (e.g., alkynes, CS2) providing insights into how these molecules interact with the nitrogenase FeMo-cofactor active site. More recently, substrate-derived species have been trapped at high concentrations during the reduction of N2, a diazene, and hydrazine, providing the first insights into binding modes and possible mechanisms for N2 reduction. A comparison of the current state of knowledge of the trapped species arising from non-physiological substrates and nitrogenous substrates is beginning to reveal some of the intricacies of how nitrogenase breaks the N2 triple bond.
A novel TFT with a laterally engineered bandgap for of 3D logic and flash memory (2010)

A dopant segregated Schottky barrier (DSSB) TFT SONOS device is demonstrated for the application of 3D TFT logic devices and flash memory. To apply the DSSB to 3D TFT flash memory, a novel spacer-free structure is successfully implemented. The DSSB TFT SONOS shows a good distribution of programmed V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">T</sub> by one-time programming with high-speed (a V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">T</sub> shift of 2.9 V @ 32 ns) due to the use of a unique local injection of carriers from the DSSB S/D junctions and it is not affected by grain boundaries. Moreover, the program speed is accelerated by reduction of the fin width owing to the enhanced field.
Protein, cDNA, and genomic DNA sequences of the towel gourd trypsin inhibitor. A squash family inhibitor. (1993)

Two trypsin inhibitor components of the squash family were isolated and purified from the juice of the towel gourd (Luffa cylindrica) using anhydrotrypsin affinity chromatography followed by high pressure liquid chromatography. The inhibitors were sequenced and found to consist of 28 and 29 amino acid residues. The determined sequences show high similarity to other inhibitors of the squash family, especially in the location of disulfide bonds and the reactive site and also in the COOH-terminal region. A cDNA library of towel gourd was constructed and used as a template for polymerase chain reaction amplification of two cDNA fragments of the inhibitor with an overlapping sequence. A full-length cDNA sequence coding for the inhibitor was then completed. The open reading frame codes for a prepro-inhibitor protein with the pre- and pro-peptides consisting of 21 and 13 residues, respectively. The deduced amino acid sequence of 29 residues for the inhibitor is consistent with that determined by primary structure analysis. The genomic sequence of the mature inhibitor was also ascertained using the total DNA of the towel gourd as a polymerase chain reaction template. The genomic sequence is completely identical with that of the cDNA, showing no intervening sequence.
Immunogold localization of phytoene desaturase in higher plant chloroplasts (1993)

In situ location of phytoene desaturase, a key enzyme in the carotenoid biosynthesis pathway, has been investigated in chloroplasts from higher plants. For this purpose, an antiserum has been raised against the phytoene desaturase from the cyanobacterium Synechococcus PCC 7942 overexpressed in E. coli . The specifity of this antiserum was demonstrated by inhibition of the enzymatic desaturation reaction in vitro. The antiserum was further purified and immunoabsorbed with E. coli proteins. The resulting IgG‐fraction was tested by western blotting against membrane proteins from chloroplasts of tobacco ( Nicotiana tabacum L. cv. Samsun) and spinach ( Spinacia oleracea L. cv. Atlanta). Apparent molecular masses of immunoreactive proteins were 62 and 64 kDa. A western blot of different membrane fractions of spinach chloroplasts (inner and outer envelopes, and thylakoids) indicated a localization of the phytoene desaturase in thylakoids. A post embedding immunogold microscopy procedure was employed. In these experiments the main labelling (79%) was associated with thylakoid membranes of tobacco chloroplasts. Of the counted colloidal gold particles, 16% were found in the stroma. Only 5% were detected in the envelope membranes. These results give clear evidence that at least the majority of phytoene desaturase molecules is localized within thylakoid membranes of higher plant chloroplasts and that the presence of the enzyme in the envelope is of minor significance.
Simulation of biatrial conduction via different pathways during sinus rhythm with a detailed human atrial model (2012)

In order to better understand biatrial conduction, investigate various conduction pathways, and compare the differences between isotropic and anisotropic conductions in human atria, we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model. In addition to known pathways: (1) Bachmann's bundle (BB), (2) limbus of fossa ovalis (LFO), and (3) coronary sinus (CS), we also hypothesize that there exist two fast conduction bundles that connect the crista terminalis (CT), LFO, and CS. Our simulation demonstrates that use of these fast conduction bundles results in a conduction pattern consistent with experimental data. The comparison of isotropic and anisotropoic conductions in the BB case showed that the atrial working muscles had small effect on conduction time and conduction speed, although the conductivities assigned in anisotropic conduction were two to four times higher than the isotropic conduction. In conclusion, we suggest that the hypothesized intercaval bundles play a significant role in the biatrial conduction and that myofiber orientation has larger effects on the conduction system than the atrial working muscles. This study presents readers with new insights into human atrial conduction.
Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-Disubstituted Ketones (2013)

The first enantioselective Ni-catalyzed reductive acyl cross-coupling has been developed. Treatment of acid chlorides and racemic secondary benzyl chlorides with a Ni(II)/bis(oxazoline) catalyst in the presence of Mn(0) as a stoichiometric reductant generates acyclic α,α-disubstituted ketones in good yields and high enantioselectivity without requiring stoichiometric chiral auxiliaries or pregeneration of organometallic reagents. The mild, base-free reaction conditions are tolerant of a variety of functional groups on both coupling partners.
The role of pancreatic stellate cells and cytokines in the development of chronic pancreatitis. (2004)

Chronic pancreatitis is a disease whose pathomechanism has not yet been fully explained. Some progress has been made in recent years, however, mainly due to the identification and description of pancreatic stellate cells (PSCs). In 1998 Bachem observed that the vitamin A-storing cells present in the pancreas, when subjected to activation, transformed into myofibroblasts capable of producing collagens I and II and fibronectin, which contributes to fibrosis in chronic pancreatitis. The development of chronic pancreatitis also seems likely to be affected by the cytokines, among other things, as a result of repeated PSC activation. The current literature provides more and more data suggesting that cytokines play an important role in the regulation of inflammation and fibrosis in CP. A major role in the pathogenesis of chronic pancreatitis is attributed to interleukin 1, 6, 10, tumour necrosis factor a (TNF-a) and transforming growth factor b1 (TGF-b1). All these factors have pro- and anti-inflammatory effects, and act simultaneously. Their effects on PSCs can be synergistic, antagonistic or complementary. Further comprehensive studies are needed to determine precisely the role of the individual cytokines and PSCs, as well as their relationships. However, the present state of our knowledge suggests that repeated episodes of AP and thus exposure to increased cytokine secretion may contribute to persistent chronic activation of PSCs, resulting in pancreatic fibrosis and chronic pancreatitis.
Turbo codes for high order constellations (2002)

The feasibility of the extension of the original turbo codes to higher rate systems is investigated. Extension to the 8-PSK constellation is given as an example. The theoretical critical SNR to achieve one and two bits per 2-D symbol is calculated for 8-PSK with the Blahut-Arimoto algorithm, thus taking into consideration the additional loss due to selecting a finite signaling set. Codes for 8-PSK that achieve 2 bits/s/Hz, within a fraction of a decibel of the theoretic limit are presented. The decoder modifications described may be directly applied to constellations with large cardinality other than 8-PSK.
Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. (2003)

Most prostate cancers (PCs) become resistant to combined androgen blockade therapy with surgical or medical castration and antiandrogens after several years. Some of these refractory PCs regress after discontinuation of antiandrogen administration [antiandrogen withdrawal syndrome (AWS)]. Although the molecular mechanisms of the AWS are not fully understood because of the lack of suitable experimental models, one hypothesis of the mechanism is mutation of androgen receptor (AR). However, bicalutamide, which has become the most prevalent pure antiandrogen, does not work as an agonist for any mutant AR detected thus far in PC. To elucidate the mechanisms of the AWS, we established and characterized novel LNCaP cell sublines, LNCaP-cxDs, which were generated in vitro by culturing androgen-dependent LNCaP-FGC human PC cells in androgen-depleted medium with bicalutamide to mimic the combined androgen blockade therapy. LNCaP-FGC cells did not grow at first, but they started to grow after 6-13 weeks of culture. Bicalutamide stimulated LNCaP-cxD cell growth and increased prostate-specific antigen secretion from LNCaP-cxD cells both in vitro and in vivo. Sequencing of AR transcripts revealed that the AR in LNCaP-cxD cells harbors a novel mutation in codon 741, TGG (tryptophan) to TGT (cysteine; W741C), or in codon 741, TGG to TTG (leucine; W741L), in the ligand-binding domain. Transactivation assays showed that bicalutamide worked as an agonist for both W741C and W741L mutant ARs. Importantly, another antiandrogen, hydroxyflutamide, worked as an antagonist for these mutant ARs. In summary, we demonstrate for the first time that within only 6-13 weeks of in vitro exposure to bicalutamide, LNCaP-FGC cells, whose growth had initially been suppressed, came to use bicalutamide as an AR agonist via W741 AR mutation to survive. Our data strongly support the hypothesis that AR mutation is one possible mechanism of the AWS and suggest that flutamide might be effective as a second-line therapy for refractory PC previously treated with bicalutamide.
Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats. (1981)

Cyclosporin A (CS-A), a selective inhibitor of T lymphocytes, is reported here to prevent S antigen (S-Ag) induced uveitis in Lewis rats. The S-Ag, found in all mammalian retinas, is uveitogenic under experimental conditions and patients with certain uveitic entities demonstrate cell mediated responses to this antigen. Daily treatment with CS-A (10 mg/kg) begun on the same day as S-Ag immunization totally inhibited the development of the uveitis in this experimental autoimmune model. Moreover a greater CS-A dose (40 mg/kg) efficiently prevented the disease process when therapy was started 7 d after S-Ag immunization. Anti-S-Ag antibody titers were observed to be similar in rats either protected or not protected with CS-A. Our data support strongly the need for T cell participation in this disease model. Since ocular inflammatory disease is an important cause of visual impairment, the data further suggest that CS-A may be useful in the treatment of patients with intractable uveitis.