gebhart/patrepeval huggingface dataset:
The P2Y 12 receptor as a therapeutic target in cardiovascular disease (2001)

Coronary thrombosis complicating rupture of atherosclerotic plaque is the predominant cause of acute coronary syndromes and platelets play a crucial role in this thrombus formation. Whilst aspirin has been successful in reducing cardiovascular morbidity and mortality, appreciation of its limited antiplatelet effects has stimulated the search for more effective antiplatelet agents. The thienopyridines, ticlopidine and clopidogrel, act, via metabolites, on the platelet ADP receptor subtype now designated P2Y(12 )(formerly P(2T), P2T (AC), P2Y (ADP) or P2Y(cyc)) and these agents have proven clinical efficacy. Analogues of the natural P2Y(12) receptor antagonist ATP have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADPinduced platelet activation, aggregation and secretion and also antagonises platelet responses, including procoagulant activity, induced by all other agonists in view of the central role of the P2Y(12) receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with clopidogrel. Orally active ATP analogues are also being developed that may be more effective than clopidogrel. Limitations of platelet glycoprotein IIb/IIIa antagonists leave scope for development of alternative antiplatelet agents.
RF telemetry powering and control of hermetically sealed integrated sensors and actuators (1990)

An RF telemetry system for powering and control of microminiature integrated transducers packaged in a hermetically sealed custom-made glass capsule is described. A class-E power amplifier is utilized to energize and control a single-channel microstimulator for neuromuscular applications. The transmitter can deliver 1.5 W of power through a solenoid antenna using a 12-V rechargeable battery, while achieving efficiencies greater than 90%. The microstimulator antenna is a 1.5-mm-diameter, 4-5-mm-long ferrite-cored solenoid coil which can generate peak voltages of up to 50 V, and up to 50 mW of power. A custom-made glass capsule electrostatically bonded to the microstimulator's silicon carrier provides a hermetic package for the implant. Lead transfer into the sealed chamber is achieved using thin films of iridium insulated with low-pressure chemical vapor deposition (LPCVD) thin films. Helium leak tests on these structures show leak rates below 10/sup -9/ cm/sup 3//s.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Fragile X syndrome, the Fragile X related proteins, and animal models (2002)

The Fragile X syndrome (FraX), which is characterized among other physical and neurologic impairments by mental retardation, is caused by the absence of the product of the FMR1 gene. The Fragile X Mental Retardation Protein (FMRP) is a member of a novel family of RNA-binding proteins. The latter includes two other proteins highly homologous with FMRP: the fragile X related proteins 1 and 2 (FXRP1 and FXRP2). Characterization of FXRPs, including their interaction with FMRP, will provide critical information about the mechanisms of action of FMRP and the role of this group of proteins in FMRP-deficient conditions such as FraX. Genetic manipulations of FMRP and the FXRPs should also provide valuable tools for investigating pathophysiology and gene therapies in FraX. The present review summarizes the strategies used for identifying the FXRPs, their chromosomal localization, molecular structure, and tissue distribution. It also reviews interactions between different members of this family of RNA-binding proteins. Animal models, both knockout and transgenic, of FMRP and the FXRPs are discussed. Phenotypic features of the FMR1 knockout mouse, the FMR1 transgenic rescue mouse, and other novel strategies for manipulating and delivering FMRP and FXRPs to the brain and other tissues are described.
Tomato Spotted Wilt Virus Resistance in Chrysanthemum Expressing the Viral Nucleocapsid Gene (1998)

Three tomato spotted wilt virus (TSWV) nucleocapsid (N) gene constructs were employed for Agrobacterium-mediated transformation of chrysanthemum (Dendranthema grandiflora) cv. Polaris. These constructs contained either a full-length N gene (pTSWVN+), a full-length N gene encoding a truncated N protein (pTSWVNt), or an antisense version of the full-length N gene (pTSWVN-), all derived from a dahlia isolate of TSWV (TSWV-D). Initial resistance screens were conducted on cuttings made from 152 pTSWVN+, 37 pTSWVNt, and 47 pTSWVN- transformed plants employing a highly virulent, heterologous strain of TSWV (TSWV-GB) isolated from chrysanthemum and vectored by thrips. This screening served to eliminate the majority of TSWV-susceptible transgenic lines. More rigorous resistance tests with three rounds of mechanical inoculation with TSWV-GB identified one pTSWVNt and two pTSWVN- transformed lines that exhibited a total lack of systemic symptoms and no virus accumulation. Six other lines, including some pTSWVN+, exhibited a lack of one or more of the destructive necrotic TSWV symptoms (stem canker and apical bud death) and a delay in symptom expression. Both sense and antisense constructs, therefore, were found to be effective at yielding TSWV resistance in chrysanthemum. Molecular analysis revealed that the highly TSWV-resistant pTSWVNt line had no detectable levels of N protein. All three resistant lines had low levels of N gene transcript and at least three transgene insertion sites within their genomes, although susceptible lines often had a similar number of insertion sites. The generation of Polaris lines resistant to TSWV transmitted either mechanically or by thrips represents the first time a major ornamental crop has been genetically engineered for disease resistance.
GGDEF and EAL domains inversely regulate cyclic di‐GMP levels and transition from sessility to motility (2004)

Summary Cyclic nucleotides represent second messenger molecules in all kingdoms of life. In bacteria, mass sequencing of genomes detected the highly abundant protein domains GGDEF and EAL. We show here that the GGDEF and EAL domains are involved in the turnover of cyclic‐di‐GMP (c‐di‐GMP) in vivo whereby the GGDEF domain stimulates c‐di‐GMP production and the EAL domain c‐di‐GMP degradation. Thus, most probably, GGDEF domains function as c‐di‐GMP cyclase and EAL domains as phosphdiesterase. We further show that, in the pathogenic organism Salmonella enterica serovar Typhimurium, the nosocomial pathogen Pseudomonas aeruginosa and the commensal species Escherichia coli , GGDEF and EAL domains mediate similar phenotypic changes related to the transition between sessility and motility. Thus, the data suggest that c‐di‐GMP is a novel global second messenger in bacteria the metabolism of which is controlled by GGDEF and EAL domain proteins.
Glasslike Arrest in Spinodal Decomposition as a Route to Colloidal Gelation (2005)

Colloid-polymer mixtures can undergo spinodal decomposition into colloid-rich and colloid-poor regions. Gelation results when interconnected colloid-rich regions solidify. We show that this occurs when these regions undergo a glass transition, leading to dynamic arrest of the spinodal decomposition. The characteristic length scale of the gel decreases with increasing quench depth, and the nonergodicity parameter exhibits a pronounced dependence on scattering vector. Mode coupling theory gives a good description of the dynamics, provided we use the full static structure as input.
Matrix-assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry-based Detection of Microsatellite Instabilities in Coding DNA Sequences: A Novel Approach to Identify DNA-Mismatch Repair-deficient Cancer Cells (2003)

Because of its reliability, short run times, and low costs, this semiquantitative procedure represents an effective alternative, in particular for diagnostic high-throughput typing of MSIs in neoplastic lesions.
Immunoglobulin Gamma-Like Therapeutic Bispecific Antibody Formats for Tumor Therapy (2019)

Bispecific antibodies (BsAbs) are a sort of dual functional proteins with specific binding to two distinct targets, which have become a focus of interest in antibody engineering and drug development research and have a promising future for wide applications in cancer immunotherapy and autoimmune disease. The key of clinical application and commercial-scale manufacturing of BsAbs is the amenability to assembly and purification of desired heterodimers. Advances in genetic engineering technology had resulted in the development of diverse BsAbs. Multiple recombinant strategies have been used to solve the mispairing problem between light and heavy chains, as well as to enforce accurate dimerization of heterologous heavy chains. There are 23 platforms available to generate 62 BsAbs which can be further divided into IgG-like ones and fragment-based ones, and more than 50 molecules are undergoing clinical trials currently. BsAbs with IgG-like architecture exhibit superior advantages in structure (similar to natural antibodies), pharmacokinetics, half-life, FcR-mediated function, and biological activity. This review considers various IgG-like BsAb generation approaches, summarizes the clinical applications of promising new BsAbs, and describes the mechanism of BsAbs in tumor therapy.
Regional cancer chemotherapy. (1984)

Regional cancer chemotherapy is a means of exploiting dose-response effects by delivering more drug to regionally confined tumors. Regional chemotherapy can be divided into two major categories, third-space (cerebrospinal, peritoneal, pleural, and pericardial fluid) and intra-arterial treatments. Interest in regional chemotherapy has risen recently for a variety of reasons, including evidence for significantly higher response rates compared to systemic therapies. The applicable pharmacokinetic principles for drug selection have been defined and indicate that regional drug exposure advantage is directly proportional to total-body drug clearance and is inversely proportional to rate of egress from a third-space or to regional blood flow. Reliable drug delivery to the entire region in question is important. The recently introduced totally implanted devices (pumps and ports) make regional therapy more reliable, safe, and convenient. In addition, nuclear medicine scanning techniques have proven useful in assessing drug distribution with regional delivery. Regional therapy may control regional tumor, but extraregional failure may ensue. However, when regional therapy is regionally selective in its toxic effects, systemic therapy may be combined in full doses. Future efforts will need to focus on the development of more potent regional therapies, alone and in combination with systemic therapies, as well as on the validation of such treatments through controlled clinical trials.
Differentiating therapy with all-trans retinoic acid in acute myeloid leukemia. (1996)

The standard treatment of patients with acute myeloid leukemia (AML) has depended on the elimination of the leukemic clone with cytotoxic myeloablation. Differentiation therapy is receiving increasing attention due to the remarkable activity of a vitamin A derivative, all-trans retinoic acid (ATRA), in patients with acute promyelocytic leukemia (APL). The majority of patients treated have achieved complete remission and with rapid resolution of the life-threatening bleeding diathesis. Phase II studies with ATRA in APL indicate certain limitations in the therapeutic use of retinoic acid. Patients achieving complete remission with ATRA alone require postremission chemotherapy, once remission is achieved, to extend remission. The results of differentiating therapy in APL patients has encouraged the use of differentiating therapy in patients with non-M3 AML. A number of areas await research, such as the need to develop ways to overcome acquired retinoic resistance and the development of cytochrome P450 inhibitors. Other novel retinoids, such as 9-cis-retinoic acid, may be even more effective than ATRA in APL. Additional important areas of research involve studying combinations of retinoids and other putative differentiating agents, and identifying different selected treatments targeted at specific molecular defects.
Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson's disease? (2002)

Human embryonic stem (ES) cells entered the popular lexicon during the political debate of summer 2001 and the decision by President George Bush to allow federal funding for research on the 64 human ES cell lines that had been derived by the day of his speech. Before the policy decision, the National Institutes of Health did a comprehensive review of the field (http://www.nih.gov/news/stemcell/scireport.htm). Human ES cells come from preimplantation embryos, most of which are generated at in vitro fertilization clinics (1). Within days after fertilization, the embryo consists of a hollow sphere, the blastocyst, which contains a cluster of a few hundred identical cells called the inner cell mass that can eventually develop into a fetus. When removed from the blastocyst, these cells can be propagated indefinitely in specialized media (2). When the media are changed to allow differentiation, cells continue to divide and aggregate, forming embroid bodies. Although these cell clusters lack the organization of an embryo, they contain all tissue types including skin, muscle, bone, and neurons. Because ES cells can become any cell in the body, there is hope that they will lead to treatment for diseases like diabetes, Parkinson's, Alzheimer's, and heart failure. The problem is controlling cell growth and differentiation. If large numbers of ES cells are transplanted into an organ like the brain, they grow into every cell type and form tumor-like masses called teratomas, eventually killing their host. How can ES cells be restricted to produce useful cells without overgrowing? In their article in this issue of PNAS, Bjorklund et al. (3) have transplanted small numbers of partially differentiated mouse ES cells from embroid bodies into a rat model of Parkinson's disease and have shown that at least some of the cells become the dopamine neurons that are needed to reverse the Parkinson …
Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships (2000)

During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the carrier protein referred to as the anandamide transporter (ANT). The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.
Cholesterol and coronary heart disease: a perspective (1985)

In this issue ofTHE JOURNALis the statement of the National Institutes of Health Consensus Development Conference on lowering blood cholesterol<sup>1</sup>; their recommendations are reasonable and can be supported. However, it is important at this point to review certain related issues. There is no doubt that elevated blood cholesterol levels and other "high-risk" factors, such as cigarette smoking, high blood pressure, obesity, physical inactivity, male sex, stressful lifestyle, and strong family history, are associated with an increased risk of development of coronary artery disease. However, even if all the recognized risk factors were eliminated except for the male sex, coronary atherosclerosis and death from coronary artery disease will<i>not</i>disappear. Therefore, it needs to be recognized that we do<i>not</i>yet know the cause(s) of coronary atherosclerosis<sup>2</sup>and there is a need for continued research to discover the cause(s) and specific treatment of coronary atherosclerosis. The recent interest,
Nucleation Enhancement of Al Alloys by High Intensity Ultrasound (2009)

The utilization of ultrasound is expected to be applied to many casting process because of the high efficiency of ultrasound energy. The present study attempts to evaluate the effect of ultrasound energy on microstructure of castings, and high intensity ultrasound was injected into A356 and A390 alloy melt for refinement of primary phase without adding a chemical refiner. The microstructure refinement, especially primary alpha phase, could not be achieved in A356 alloy with simply ultrasound injection into alloy melt, although ultrasound was injected for 20 min. However, the influence of ultrasound on the microstructure in A390 alloy is very clear. Primary silicon of A390 alloy with ultrasound injection into melt was very small and dispersed uniformly in alloy matrix. In addition, the primary Si size was decreased with an increase the ultrasound injection time from 82 to 8 µm. As compared with A356 alloy, however, A390 alloy shows the nucleation enhancement by ultrasound vibration of melt only. The reason that there is a difference of the refinement of primary phase between A356 and A390 alloy could be explained by solute cluster theory.
Ignavine: a novel allosteric modulator of the μ opioid receptor (2016)

Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR. Receptor internalization assay in MOR-expressing cell lines revealed that ignavine augmented the responses produced by D-Ala(2)-N-Me-Phe(4)-Gly-ol(5)-enkephalin (DAMGO), a representative MOR agonist, at a low concentration and inhibited it at a higher concentration. Ignavine also exerted positive modulatory activity for DAMGO, endomorphin-1 and morphine in cAMP assay. Additionally, ignavine alone showed an analgesic effect in vivo. In silico simulation analysis suggested that ignavine would induce a unique structural change distinguished from those induced by a representative MOR agonist and antagonist. These data collectively suggest the possibility that ignavine could be a novel allosteric modulator of the MOR. The present results may open the way for the development of a novel pain management strategy.
Instant user interfaces (2013)

Dedicated input devices are frequently used for system control. We present Instant User Interfaces, an interaction paradigm that loosens this dependency and allows operating a system even when its dedicated controller is unavailable. We implemented a reliable, marker-free object tracking system that enables users to assign semantic meaning to different poses or to touches in different areas. With this system, users can repurpose everyday objects and program them in an ad-hoc manner, using a GUI or by demonstration, as input devices. Users tested and ranked these methods alongside a Wizard-of-Oz speech interface. The testers did not show a clear preference as a group, but had individual preferences.
Diode pumped parametric chirped pulse amplification system with mJ output energies (2000)

120 pJ and 300 fs pulses from an Er-fiber oscillator are amplified up to 1.8 mJ of energy (~70 dB gain) and up to 2.8 W of average power after a single-pass through 2 cm long periodically poled LiNbO3 (PPLN) crystal in a diode pumped parametric chirped pulse amplification system.
Genome sequence and analysis of the tuber crop potato (2011)

Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.
Room-temperature synthesis of cyclometalated iridium(iii) complexes: kinetic isomers and reactive functionalities (2013)

Cyclometalated iridium(III) complexes have been prepared in high yields from base-assisted transmetalation reactions of cis-bis(aquo)iridium(III) complexes with boronated aromatic proligands. Reactions proceed at room temperature. Potassium hydroxide and potassium phosphate are effective supporting bases. Kinetic, meridional isomers are isolated because of the mildness of the new technique. Syntheses are faster with KOH, but the gentler base K3PO4 broadens the reaction's scope. Complexes of chelated ketone, aldehyde, and alcohol complexes are reported that bind iridium through formally neutral oxygen and formally anionic carbon. The new complexes luminesce with microsecond-scale lifetimes at 77 K and nanosecond-scale lifetimes at room temperature; emission quenches in air. Two complexes, an aldehyde and its reduced (alcohol) derivative, are crystallographically characterized. Their bonding is examined with density-functional theory calculations. Time-dependent computations suggest that the Franck–Condon triplet states of these complexes have mixed orbital parentage, arising from one-particle transitions that mingle through configuration interaction.