gebhart/patrepeval huggingface dataset:
Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes. (1995)

The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Prospective evaluation of surgical microscope—integrated intraoperative near-infrared indocyanine green videoangiography during aneurysm surgery (2005)

Microscope-based ICG videoangiography is simple and provides real-time information about the patency of vessels of all sizes and about the aneurysm sac. This technique may be useful during routine aneurysm surgery as an independent form of angiography or as an adjunct to intra- or postoperative DS angiography.
Activated Singlet Exciton Fission in a Semiconducting Polymer (2013)

Singlet exciton fission is a spin-allowed process to generate two triplet excitons from a single absorbed photon. This phenomenon offers great potential in organic photovoltaics, but the mechanism remains poorly understood. Most reports to date have addressed intermolecular fission within small-molecular crystals. However, through appropriate chemical design chromophores capable of intramolecular fission can also be produced. Here we directly observe sub-100 fs activated singlet fission in a semiconducting poly(thienylenevinylene). We demonstrate that fission proceeds directly from the initial 1Bu exciton, contrary to current models that involve the lower-lying 2Ag exciton. In solution, the generated triplet pairs rapidly recombine and decay through the 2Ag state. In films, exciton diffusion breaks this symmetry and we observe long-lived triplets which form charge-transfer states in photovoltaic blends.
Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma (2002)

CD30 is an excellent target for immunotherapy of Hodgkin lymphoma (HL) because it is overexpressed on Hodgkin and Reed-Sternberg cells. We developed a novel bispecific molecule (BSM) consisting of F(ab') fragments derived from the murine anti-CD30 monoclonal antibody (MoAb) Ki-4 and the humanized CD64-specific MoAb H22. In vitro experiments of H22xKi-4 demonstrated specific phagocytosis of HL-derived cell lines. Patients (pts) with refractory CD30(+) HL were treated with escalating doses of H22xKi-4 at doses of 1, 2.5, 5, 10, and 20 mg/m(2)/d, respectively (administered intravenously on days 1, 3, 5, and 7). The main study objectives were to determine the maximum tolerated dose and the dose-limiting toxicities of H22xKi-4, to define its pharmacokinetic profile, and to document clinical response. Ten pts were enrolled and are evaluable for toxicity and response. Side effects were transient and mild with hypotension (4 of 10), tachycardia (6 of 10), fatigue (10 of 10), and fever (2 of 10 grade I, 3 of 10 grade II). Pharmacokinetic (PK) data revealed an elimination half-life of 11.1 hours, resulting in a significant accumulation of H22xKi-4. The BSM was shown to bind to both monocytes and malignant cells. Response to H22xKi-4 included 1 complete remission (CR), 3 partial remissions (PR), and 4 pts with stable disease. The new BSM H22xKi-4 can be given safely to pts with refractory CD30(+) HL in doses up to 80 mg/m(2) per cycle. Although this dose is not the maximum tolerated dose (MTD) as defined by toxicity criteria, surrogate parameters suggest a biologic effective regimen. H22xKi-4 shows activity in heavily pretreated HL patients warranting further clinical evaluation.
Growth of Orthorhombic SnS Nanobox Structures on Seeded Substrates (2010)

Tin sulfide (SnS) nanostructures have been synthesized using a simple and low temperature chemical solution method on seeded substrates, and their structural and optical properties have been investigated. The as-grown SnS nanostructures with well-defined facets exhibited good stoichiometry between constituent elements. These nanobox structures are preferentially oriented along the [010] direction by having [100] and [001] orientations as surrounding facets and exhibited two distinguishable optical band gaps of 1.36 and 1.9 eV. The effect of solution concentration as well as seed layer on the morphology of SnS structures has also been studied, and finally, the growth mechanism of the regular SnS nanobox structures is proposed.
Full-wave vector Maxwell equation modeling of the self-focusing of ultrashort optical pulses in a nonlinear Kerr medium exhibiting a finite response time (1993)

The extension of the conventional finite-difference time-domain solution of the full vector Maxwell equations to modeling femtosecond optical-pulse propagation in a nonlinear Kerr medium that exhibits a finite response time is presented. Numerical results are given for nonlinear self-focusing in two space dimensions and time; the technique can be generalized to three space dimensions with adequate computer resources. Comparisons with previously reported and anticipated results are made. Several novel phenomena that are not observed with scalar models of self-focusing and that can be attributed only to the complete solution of the vector Maxwell equations are discussed.
Developmental Performance of an Egg Injection Machine for Administration of Marek's Disease Vaccine (1993)

The results of these studies show the progression in the development of the INOVOJECT® system for the in ovo administration of Marek's disease vaccine to commercial broiler eggs (embryos). The initial studies were conducted using a large egg injection machine prototype and in subsequent studies a smaller prototype. Statistical and numerical analysis of the results showed that hatchability, two-week mortality, livability to the time of processing, and live body weight were similar for both the INOVOJECT® treatment and the conventional treatment. The INOVOJECT® treatment consistently (six of seven studies) resulted in lower feed conversion ratios and reduced settlement costs compared to the conventional treatment. Finally, the leucosis and total condemnations were similar in the INOVOJECT® treatment compared to the conventional treatment, a factor which demonstrates the field efficacy of in ovo administration of Marek's disease vaccine.
Error-free and error-prone lesion bypass by human DNA polymerase kappa in vitro (2000)

Error-free lesion bypass and error-prone lesion bypass are important cellular responses to DNA damage during replication, both of which require a DNA polymerase (Pol). To identify lesion bypass DNA polymerases, we have purified human Polkappa encoded by the DINB1 gene and examined its response to damaged DNA templates. Here, we show that human Polkappa is a novel lesion bypass polymerase in vitro. Purified human Polkappa efficiently bypassed a template 8-oxoguanine, incorporating mainly A and less frequently C opposite the lesion. Human Polkappa most frequently incorporated A opposite a template abasic site. Efficient further extension required T as the next template base, and was mediated mainly by a one-nucleotide deletion mechanism. Human Polkappa was able to bypass an acetylaminofluorene-modified G in DNA, incorporating either C or T, and less efficiently A opposite the lesion. Furthermore, human Polkappa effectively bypassed a template (-)-trans-anti-benzo[a]pyrene-N:(2)-dG lesion in an error-free manner by incorporating a C opposite the bulky adduct. In contrast, human Polkappa was unable to bypass a template TT dimer or a TT (6-4) photoproduct, two of the major UV lesions. These results suggest that Polkappa plays an important role in both error-free and error-prone lesion bypass in humans.
Epithelial Na+ channel subunits in rat taste cells: Localization and regulation by aldosterone (1999)

Amiloride-sensitive Na+ channels play an important role in transducing Na+ salt taste. Previous studies revealed that in rodent taste cells, the channel shares electrophysiological and pharmacological properties with the epithelial Na+ channel, ENaC. Using subunit-specific antibodies directed against alpha, beta, and gamma subunits of rat ENaC (rENaC), we observed cytoplasmic immunoreactivity for all three subunits in nearly all taste cells of fungiform papillae, and in about half of the taste cells in foliate and vallate papillae. The intensity of labeling in cells of vallate papillae was significantly lower than that of fungiform papillae, especially for beta and gamma subunits. Dual localization experiments showed that immunoreactivity for the taste cell-specific G protein, gustducin, occurs in a subset ofrENaC positive taste cells. Aldosterone is known to increase the amiloride sensitivity of the NaCl taste response. In our study, increases in blood aldosterone levels enhanced the intensity of apical immunoreactivity for beta and gamma rENaC in taste cells of all papillae. In addition, whole cell recordings from isolated taste cells showed that in fungiform papillae, aldosterone increased the number of amiloride-sensitive taste cells and enhanced the current amplitude. In vallate taste cells, which are normally unresponsive to amiloride, aldosterone treatment induced an amiloride sensitive current in about half of the cells. Immunoreactivity for rENaC subunits also was present in nonsensory epithelial cells, especially in the anterior portion of the tongue. In addition, immunoreactivity for all subunits, but especially beta and gamma, was associated with some nerve fibers innervating taste papillae. These extragustatory sites of rENaC expression may indicate a role for this channel in paracellular transduction of sodium ions.
The C(H)1 domain of IgG is not essential for C3 covalent binding: importance of the other constant domains as targets for C3. (1998)

The covalent binding of C3 to antigen-antibody complexes [immune complexes (IC)] plays a pivotal role in the elimination of antigens. C3 prevents the formation of large IC lattices promoting their solubilization. Subsequently, bound C3 fragments determine the efficacy of antigen presentation, and the generation of antibody responses and immunological memory. C3 binding to IgG-IC generates IgG-C3b-C3b complexes which are detected by SDS-PAGE as two major bands: C3alpha65-heavy chain and C3alpha65-C3alpha43 covalent complexes. Using human heat-aggregated IgG1 as a model of IC, a C3b binding site was localized only in the Cgamma1 domain. However, with true IC of ovalbumin and rabbit IgG anti-ovalbumin, C3b binds to both the Fab and Fc regions of IgG. To study the binding of C3b to the different domains of IgG and particularly to evaluate the involvement of the Cgamma1 domain, we have constructed recombinant single-chain antibodies without Cgamma1, which have the structure: V(H)-linker-V(L)-hinge-Cgamma2-Cgamma3 (scAb). The variable domains were from a mouse mAb anti-HSA and the constant region (hinge-C(H)2-C(H)3) from human IgG1 or rabbit IgG. C3 binds very efficiently to IC formed with human (h-scAb) or rabbit (r-scAb) recombinant antibodies (scAb-HSA) and generates also two bands on SDS-PAGE (C3alpha65-scAb and C3alpha65-C3alpha43), which are the counterparts of those of the complete antibody. In addition, IC formed with scAb activate the alternative pathway to a similar extent as IC of the entire IgG. These data indicate that the Cgamma1 domain is a dispensable region for C3b binding and that the remaining constant domains are as efficient as Cgamma1 in C3b binding. Overall these results support the view that C3 does not specifically recognize a unique site in the Cgamma1 domain. Rather it seems to be able to attach along the antibody molecule. Probably this implies an advantage for effective processing of C3b-IC and elimination of antigens in vivo.
Dietary soy-phytoestrogens decrease testosterone levels and prostate weight without altering LH, prostate 5alpha-reductase or testicular steroidogenic acute regulatory peptide levels in adult male Sprague-Dawley rats (2001)

Nutritional factors, especially phytoestrogens, have been extensively studied for their potential beneficial effects against hormone-dependent and age-related diseases. The present study describes the short-term effects of dietary phytoestrogens on regulatory behaviors (food/water intake, locomotor activity and body weight), prostate weight, prostate 5alpha-reductase enzyme activity, reproductive hormone levels, and testicular steroidogenic acute regulatory peptide (StAR) levels in adult Sprague-Dawley rats. Animals were fed either a phytoestrogen-rich diet containing approximately 600 microg/g isoflavones (as determined by HPLC) or a phytoestrogen-free diet. After 5 weeks of consuming these diets, plasma phytoestrogen levels were 35 times higher in animals fed the phytoestrogen-rich vs phytoestrogen-free diets. Body and prostate weights were significantly decreased in animals fed the phytoestrogen-rich diet vs the phytoestrogen-free fed animals; however, no significant change in prostate 5alpha-reductase enzyme activity was observed between the treatment groups. Locomotor activity levels were higher in the phytoestrogen-rich vs the phytoestrogen-free animals during the course of the treatment interval. Plasma testosterone and androstenedione levels were significantly lower in the animals fed the phytoestrogen-rich diet compared with animals fed the phytoestrogen-free diet. However, there were no significant differences in plasma LH or estradiol levels between the diet groups. Testicular StAR levels were not significantly different between the phytoestrogen-rich vs the phytoestrogen-free fed animals. These results indicated that consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels over a relatively short period can significantly alter body and prostate weight and plasma androgen hormone levels without affecting gonadotropin or testicular StAR levels. The findings of this study identify the biological actions of phytoestrogens on male reproductive endocrinology and provide insights into the protective effects these estrogen mimics exert in male reproductive disorders such as benign prostatic hyperplasia and prostate cancer.
BRI2 Inhibits Amyloid β-Peptide Precursor Protein Processing by Interfering with the Docking of Secretases to the Substrate (2008)

Genetic alterations of amyloid beta-peptide (Abeta) production caused by mutations in the Abeta precursor protein (APP) cause familial Alzheimer's disease (AD). Mutations in BRI2, a gene of undefined function, are linked to familial British and Danish dementias, which are pathologically and clinically similar to Alzheimer's disease. We report that BRI2 is a physiological suppressor of Abeta production. BRI2 restrict docking of gamma-secretase to APP and access of alpha- and beta-secretases to their cleavage APP sequences. Alterations of BRI2 by gene targeting or transgenic expression regulate Abeta levels and AD pathology in mouse models of AD. Competitive inhibition of APP processing by BRI2 may provide a new approach to AD therapy and prevention.
Choosing a drug-eluting stent: a comparison between CYPHER and TAXUS. (2005)

For patients with coronary artery disease undergoing percutaneous intervention, drug-eluting stents (DESs) have rapidly become the standard of care. This article reviews the currently available delivery-platform/drug-carrier-vehicle combinations and those expected to become available in the future. It also evaluates and compares current DES platforms in terms of the drug involved, the delivery platform, efficacy, and safety. Currently, 2 DES platforms are available: 1 eluting sirolimus and 1 eluting paclitaxel. Sirolimus is a macrolide antibiotic with a cytostatic mechanism and an anti-inflammatory effect. Paclitaxel is a chemotherapeutic (cytotoxic) agent. The delivery platform is composed of the balloon catheter, the stent, and the drug-carrier vehicle. The carrier vehicle offers controlled drug release and enhances drug distribution. It can be a polymer that serves as a diffusion barrier or a matrix (either durable or degradable) for drug loading. Alternatively, a structural modification on the surface of the stent itself, such as a groove or well in which the drug is placed, can serve as carrier. With respect to efficacy, major trials have shown that the sirolimus platform has a lower late luminal loss rate than does the paclitaxel stent. Moreover, less intimal proliferation and obstruction occurs with the sirolimus platform than with the paclitaxel platform. Also, compared to bare metal stents, the sirolimus platform reduces late luminal loss in challenging subsets of patients. Both stents offer excellent short-term safety. To improve our understanding of these stents, a head-to-head comparison is needed.
Molecular mechanisms in nickel carcinogenesis: modeling Ni(II) binding site in histone H4. (2002)

Ni(II) compounds are well known as human carcinogens, though the molecular events which are responsible for this are not yet fully understood. It has been proposed that the binding of N(II) ions within the cell nucleus is a crucial element in the mechanism of carcinogenesis. The most abundant proteins in the cell nucleus are histones, and this makes them the prime candidates for this role. This article is a review of our recent studies of histone H4 models of Ni(II) binding. We analyzed the sequence of the N-terminal tail of the histone H4, Ac-SGRGKGGKGLGKGGAKRH(18)RKVL-Am, for Ni(II) binding. This site has been proposed mainly because of the potent inhibitory effect of Ni(II) on the acetylation of lysine residues near the histidine H(18), and also because of the accessibility of the H4 tail in the histone octamer. Combined potentiometric and spectroscopic studies showed that the histidine 18 acted as an anchoring binding site for metal ions in the peptide investigated. Comparison with the results for Cu(II) binding are also reported. The results allowed us to propose that the binding of Ni(II) is able to promote a secondary structure with organized side-chain orientation on the N-terminal tail of histone H4.
Wire segmenting for improved buffer insertion (1997)

Buffer insertion seeks to place buffers on the wires of a signal netto minimize delay. Van Ginneken [Buffer Placement in Distributed RC-tree Networks for Minimal Elmore Delay] proposed an optimal dynamicprogramming solution (with extensions proposed by [7] [8][9] [12]) such that at most one buffer can be placed on a singlewire. This constraint can hurt solution quality, but it may be circumventedby dividing each wire into multiple smaller segments.This work studies the problem of finding the correct number of segmentsfor each wire in the routing tree. Too few segments yieldssub-par solutions, but too many segments can lead to excessive runtimes and memory loads. We derive new theoretical results forcomputing the appropriate number of buffers (and hence wire segments)which motivate our new wire segmenting algorithm. Weshow that using wire segmenting as a precursor to buffer insertionproduces solutions within a few percent of optimal, while usingonly seconds of CPU time.
Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success (2005)

Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65(-/-) mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.
MUTATIONS WITH DOMINANT EFFECTS ON THE BEHAVIOR AND MORPHOLOGY OF THE NEMATODE CAENORHABDITIS ELEGANS (1986)

We have analyzed 31 mutations that have dominant effects on the behavior or morphology of the nematode Caenorhabditis elegans. These mutations appear to define 15 genes. We have studied ten of these genes in some detail and have been led to two notable conclusions. First, loss of gene function for four of these ten genes results in a wild-type phenotype; if these genes represent a random sample from the genome, then we would estimate that null mutations in about half of the genes in C. elegans would result in a nonmutant phenotype. Second, the dominant effects of mutations in nine of these ten genes are caused by novel gene functions, and in all nine cases the novel function is antagonized by the wild-type function.
Experimental Staphylococcus aureus arthritis in mice (1991)

Staphylococcus aureus arthritis is usually caused by bacteremia and is highly destructive. Controlled studies on septic arthritis in humans are difficult to perform, because the time of onset of the infection is unknown. Animal models of bacterial arthritis make it possible to control important variables in experimental studies. We present a mouse model of S. aureus arthritis in which the intravenous administration of 10(7) cells of S. aureus LS-1 induced arthritis or osteitis or both within 3 weeks in 80 to 90% of the mice. Signs of arthritis emerged within the first few days after the injection. An interesting finding was that the S. aureus strain used in this study binds bone sialoprotein, a glycoprotein known to be specifically localized to bone tissue. This new model of S. aureus arthritis enables the study of the kinetics of joint destruction and the host-bacterium relationship as well as therapeutical approaches to septic arthritis and osteomyelitis.
Active immunotherapy for advanced intracranial murine tumors by using dendritic cell-tumor cell fusion vaccines (2005)

These data indicate a strategy to achieve an antitumor response against tumors in the central nervous system that is highly focused from both immunological and anatomical perspectives.