gebhart/patrepeval huggingface dataset:
P4‐088: Central and Peripheral Pharmacokinetic and Pharmacodynamic Effects of the β‐site APP Cleavage Enzyme (BACE1) Inhibitor LY2811376 In Humans (2010)

LY2811376 is a BACE1 inhibitor with marked Aβ-lowering effects in animal models. This was a translational study. Development was interrupted in humans due to preclinical toxicity findings. The safety, pharmacodynamics and pharmacokinetics of orally administered LY2811376 was investigated in one single and one multiple ascending dose (SAD, MAD) trial in healthy volunteers. As part of SAD, the effect of 2 doses of LY2811376 on concentrations of Aβs, sAPPβ and sAPPα (‘analytes') was determined in CSF serially collected via indwelling lumbar catheter. Plasma and CSF analytes were measured by immunoassay. Plasma drug concentrations were measured by LC/MS/MS. 55 and 28 subjects completed SAD and MAD studies, respectively. Administration of single and multiple doses of LY2811376 were well tolerated. Mean terminal half-life of LY2811376 exceeded 24 hours. Subjects exposed to single doses of LY2811376 experienced dose-dependent reductions in plasma Aβ, with significant 24-hour time averaged reductions in plasma Aβ1-40 and Aβ1-X, at the highest dose. Steady-state exposure to LY2811376 from multiple daily dosing of LY2811376 similarly significantly reduced 24-hour time-averaged Aβ1-40 and Aβ1-x concentrations as compared with placebo. Aβ rebound effects were not observed. Single doses of LY2811376 produced significant dose-dependent reductions in CSF Aβ1-40 and Aβ1-42, measured at nadir, as well as significant dose dependent 24-hour time-averaged reductions. CSF sAPPβ (as proximal biomarker) and sAPPα (biomarker of compensatory alpha-secretase activation) showed significant, dose-dependent decreases and increases relative to placebo, respectively. LY2811376 produced sustained and robust reductions in plasma and CSF Aβ in subjects, confirming proof of mechanism. While the clinical development of LY2811376 is on hold, development of potent, clinically well-tolerated BACE1 inhibitors for the treatment of Alzheimer's disease appears plausible.
O4‐06‐03: An immunological epitope specific for toxic oligomeric Aß in Alzheimer's disease (2012)

Alzheimer's disease (AD) is a major threat to the autonomy, mobility, and well-being of persons in the developed world. The etiology of this disease is not yet clearly defined; however, recent work has implicated oligomers of the Aβ peptide in neurotoxicity, inhibition of synaptic plasticity, and cell-to-cell spread of AD pathology. The atomic level structure of Aβoligomers has not been conclusively solved, but biochemical, biophysical and immunochemical data suggest a fibril/oligomer model in which Aβ monomers are packed in broad b-hairpin steric zipper structures. As insoluble Aβ fibril structures possess an internal K28-D23 salt bridge, we hypothesized that soluble oligomers would favor externally oriented charged side chains. Inspection of Aβ structural models revealed solvent exposed epitopes at the Aβ N-terminus recognized by the monoclonal antibodies 6E10 and 4G8, and a constrained turn comprised of residues 25-29 (GSNKG), against which no antibody has been reported. We raised antibodies against this epitope (Fig. 1a) in mice and evaluated them with Biacore surface plasmon resonance, immunoblotting after SDS-PAGE and Blue Native-PAGE, and flow cytometry. A monoclonal antibody (5E3) raised against the cyclic GSNKG epitope binds to synthetic oligomers of Aβ with high affinity (∼7 nM), but is unreactive to monomeric Aβ or full-length amyloid precursor protein. 5E3 specifically recognizes oligomers in Alzheimer's diseased brain homogenates (Fig. 1b & c) and cerebrospinal fluid, while displaying negligible reactivity to healthy control brain and cerebrospinal fluid. 5E3 is detecting a SDS-resistant, HFIP and Proteinase K sensitive ∼56 kDa oligomer in AD brains. Analysis of 5E3 reactivity to normal mouse neurons confirmed that the novel epitope is absent from neuronal cell surfaces, unlike previously known epitopes and reactive antibodies (i.e. 6E10). Furthermore, 5E3 treatment prevented Aβ (1-40) oligomer-induced neurotoxicity in a dose-dependent manner (Fig. 1d) and stalled Aβ oligomerization in vitro.
In vitro antibacterial activities of PD 131628, a new 1,8-naphthyridine anti-infective agent (1991)

PD 131628 is a new aminopyrrolidine-substituted fluorocyclopropyl naphthyridine quinolone which possesses high in vitro activity against a wide spectrum of bacterial species. The MICs for greater than or equal to 90% of strains were 0.125 to 0.25 microgram/ml for staphylococci, Streptococcus pyogenes, and S. pneumoniae; 0.5 micrograms/ml for S. agalactiae and Enterococcus faecalis; 0.125 micrograms/ml for members of the family Enterobacteriaceae and Acinetobacter spp.; 0.5 micrograms/ml for Pseudomonas aeruginosa; and less than or equal to 0.03 micrograms/ml for Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria gonorrhoeae. In these in vitro comparisons with ciprofloxacin, PD 131628 is more active against gram-positive organisms, approximately equivalent against gram-negative organisms, and, like most other quinolones, relatively inactive against gram-negative anaerobes. In most instances, the in vitro potency of PD 131628 exceeded those of widely used compounds: ciprofloxacin, imipenem, ampicillin, penicillin G, oxacillin, cefazolin, ceftazidime, cefoxitin, cefsulodin, aztreonam, piperacillin, amikacin, spectinomycin, doxycycline, erythromycin, metronidazole, and vancomycin.
Vampire Venom: Vasodilatory Mechanisms of Vampire Bat (Desmodus rotundus) Blood Feeding (2019)

Animals that specialise in blood feeding have particular challenges in obtaining their meal, whereby they impair blood hemostasis by promoting anticoagulation and vasodilation in order to facilitate feeding. These convergent selection pressures have been studied in a number of lineages, ranging from fleas to leeches. However, the vampire bat (<i>Desmondus rotundus</i>) is unstudied in regards to potential vasodilatory mechanisms of their feeding secretions (which are a type of venom). This is despite the intense investigations of their anticoagulant properties which have demonstrated that <i>D. rotundus</i> venom contains strong anticoagulant and proteolytic activities which delay the formation of blood clots and interfere with the blood coagulation cascade. In this study, we identified and tested a compound from <i>D. rotundus</i> venom that is similar in size and amino acid sequence to human calcitonin gene-related peptide (CGRP) which has potent vasodilatory properties. We found that the vampire bat-derived form of CGRP (i.e., vCGRP) selectively caused endothelium-independent relaxation of pre-contracted rat small mesenteric arteries. The vasorelaxant efficacy and potency of vCGRP were similar to that of CGRP, in activating CGRP receptors and Kv channels to relax arteriole smooth muscle, which would facilitate blood meal feeding by promoting continual blood flow. Our results provide, for the first time, a detailed investigation into the identification and function of a vasodilatory peptide found in <i>D. rotundus</i> venom, which provides a basis in understanding the convergent pathways and selectivity of hematophagous venoms. These unique peptides also show excellent drug design and development potential, thus highlighting the social and economic value of venomous animals.
Conditions of Multiple Cracking for Polypropylene Discontitious Fiber Reinforced Cementitious Composites manufactured by Extrusion Molding (2002)

Peer Reviewed
Role of antibodies in cancer targeting (2010)

The development of chemotherapeutic agents capable of specifically eliminating tumor cells has been a great challenge since these agents cannot differentiate between normal body cells and tumor cells. Enhanced elimination of cancer cells without affecting normal body cells can be achieved by developing strategies which can enable drug targeting. With recent advances in antibody engineering strategies, the development of different antibody-associated tumor-targeted delivery systems for chemotherapy, chemoprevention, and early cancer diagnosis has become possible. In this review, the role of antibodies for cancer diagnosis, chemoprevention, and chemotherapy will be discussed with an emphasis on recent advances in antibody engineering.
Aspis: Robust Detection for Distributed Learning (2021)

State-of-the-art machine learning models are routinely trained on large-scale distributed clusters. Crucially, such systems can be compromised when some of the computing devices exhibit abnormal (Byzantine) behavior and return arbitrary results to the parameter server (PS). This behavior may be attributed to a plethora of reasons, including system failures and orchestrated attacks. Existing work suggests robust aggregation and/or computational redundancy to alleviate the effect of distorted gradients. However, most of these schemes are ineffective when an adversary knows the task assignment and can choose the attacked workers judiciously to induce maximal damage. Our proposed method Aspis assigns gradient computations to worker nodes using a subset-based assignment which allows for multiple consistency checks on the behavior of a worker node. Examination of the calculated gradients and post-processing (clique-finding in an appropriately constructed graph) by the central node allows for efficient detection and subsequent exclusion of adversaries from the training process. We prove the Byzantine resilience and detection guarantees of Aspis under weak and strong attacks and extensively evaluate the system on various large-scale training scenarios. The principal metric for our experiments is the test accuracy, for which we demonstrate a significant improvement of about 30% compared to many state-of-the-art approaches on the CIFAR-10 dataset. The corresponding reduction of the fraction of corrupted gradients ranges from 16% to 99%.
Defined microbiota transplant restores Th17/RORγt + regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas (2019)

Abstract The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases, where clinical trials of fecal microbiota transplant have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells and a deficit in the tolerogenic RORγt + Treg cell subset. Transplanting healthy donor-derived microbiota into mice colonized with human IBD microbiotas lead to induction of RORγt + Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn’s disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, correlated with a reduction in Th17 cells.
Effects of fuel injection parameters on the performance of homogeneous charge compression ignition at low-load conditions (2015)

With the objective of enhancing the effectiveness of late fuel injection strategy in extending the low-load limit of homogeneous charge compression ignition engines, a numerical study is conducted to investigate the effects of fuel injection parameters, such as the injection pressure and spray cone angle, on the overall combustion efficiency and CO/NO x emissions. Closed-cycle engine simulations are performed incorporating detailed iso-octane reaction kinetics and combustion submodel based on the spray-interactive flamelet approach. Extensive parametric studies are conducted to provide a detailed map of the combustion efficiency and emission performance. In general, it is found that the in-cylinder charge stratification can be reduced by both an increased injection pressure and a wider spray cone angle, resulting in substantially lower NO x emissions and reasonably high combustion efficiency simultaneously. The present study demonstrates that an optimal adjustment of the two fuel injection parameters can result in significant extension of the low-load limit of homogeneous charge compression ignition through delayed fuel injection strategy.
Determination of calcium and magnesium in hydroethanolic extracts of propolis by atomic absorption flame spectrophotometry (2014)

Propolis is a natural product collected by honeybees and has a large range of pharmacological activity, including antimicrobial, antitumoral, antioxidant and anti-inflammatory. Its use as a popular medicine is increasing all over the world, creating a need for quality control of the commercial products. In this study the levels of calcium and magnesium in commercial hydroalcoholic propolis extracts from varies states of Brazil were determined by atomic absorption flame spectrophotometry and different values were obtained for northern and southern states. This study can be extended to the analysis of metals that are harmful to health. The results showed that the calibration curves were linear over a wide concentration range (0.5-4.0 μg.mL -1 for calcium and 0.05-0.4 μg.mL -1 for magnesium) with good correlation coefficients (0.999 and 0.988, respectively). Good analytical recovery (94%) was obtained. The proposed method showed adequate precision and relative standard deviation lower than 2 %. The method is accurate and precise as well as having advantages such as simplicity and speed.
Total synthesis of (+)-belactosin A (2004)

A concise first total synthesis of the antitumour antibiotic belactosin A is reported, involving coupling of beta-lactone carboxylic acid 3 with N-Ala-aminocyclopropyl alanine 11.
Division polynomials of elliptic curves over finite fields (1996)

We consider an ellipic curve E over the finite field Fp for a prime p 4= 2,3.
Synthetic Principles Directing Charge Transport in Low-Band-Gap Dithienosilole–Benzothiadiazole Copolymers (2012)

Given the fundamental differences in carrier generation and device operation in organic thin-film transistors (OTFTs) and organic photovoltaic (OPV) devices, the material design principles to apply may be expected to differ. In this respect, designing organic semiconductors that perform effectively in multiple device configurations remains a challenge. Following "donor-acceptor" principles, we designed and synthesized an analogous series of solution-processable π-conjugated polymers that combine the electron-rich dithienosilole (DTS) moiety, unsubstituted thiophene spacers, and the electron-deficient core 2,1,3-benzothiadiazole (BTD). Insights into backbone geometry and wave function delocalization as a function of molecular structure are provided by density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level. Using a combination of X-ray techniques (2D-WAXS and XRD) supported by solid-state NMR (SS-NMR) and atomic force microscopy (AFM), we demonstrate fundamental correlations between the polymer repeat-unit structure, molecular weight distribution, nature of the solubilizing side-chains appended to the backbones, and extent of structural order attainable in p-channel OTFTs. In particular, it is shown that the degree of microstructural order achievable in the self-assembled organic semiconductors increases largely with (i) increasing molecular weight and (ii) appropriate solubilizing-group substitution. The corresponding field-effect hole mobilities are enhanced by several orders of magnitude, reaching up to 0.1 cm(2) V(-1) s(-1) with the highest molecular weight fraction of the branched alkyl-substituted polymer derivative in this series. This trend is reflected in conventional bulk-heterojunction OPV devices using PC(71)BM, whereby the active layers exhibit space-charge-limited (SCL) hole mobilities approaching 10(-3) cm(2) V(-1) s(-1), and yield improved power conversion efficiencies on the order of 4.6% under AM1.5G solar illumination. Beyond structure-performance correlations, we observe a large dependence of the ionization potentials of the polymers estimated by electrochemical methods on polymer packing, and expect that these empirical results may have important consequences on future material study and device applications.
Evidence‐based medicine training in residency: a survey of urology programme directors (2009)

In this survey we found that most programme directors recognize formal EBM teaching as an important aspect of urology residency training. However, most programmes devote less time to EBM training than they would like, and urology-specific resources have been lacking. These findings support increased efforts to provide urology residents with opportunities to learn EBM-related knowledge and skills in a variety of educational formats.
The metastatic T‐cell hybridoma antigen/P‐selectin glycoprotein ligand 1 is required for hematogenous metastasis of lymphomas (2007)

Using variants of the murine BW5147 lymphoma cell-line, we have previously identified 3 monoclonal antibodies (MAbs) that discriminate between metastatic and nonmetastatic BW5147-derived T-cell hybridomas and lymphomas, as well as BW5147-unrelated T-lymphomas. These MAbs were reported to recognize an identical membrane-associated sialoglycoprotein, termed "metastatic T-cell hybridoma antigen" (MTH-Ag). Here, we document that the expression pattern of the MTH-Ag on metastatic and nonmetastatic BW5147 variants correlates with that of the P-selectin glycoprotein ligand 1 (PSGL-1), a sialomucin involved in leukocyte recruitment to sites of inflammation. Moreover, the MAbs against the MTH-Ag recognize PSGL-1 when it is transfected in MTH-Ag-negative BW5147 variants, suggesting that the MTH-Ag is PSGL-1. Overexpression of MTH-Ag/PSGL-1 in MTH-Ag-negative BW5147 variants did not affect their in vivo malignancy. Yet, down-regulation of MTH-Ag/PSGL-1 expression on metastatic, MTH-Ag-positive BW5147 variants, using an RNA interference (RNAi) approach, resulted, in a dose-dependent manner, in a significant reduction of liver and spleen colonization and a delay in mortality of the recipient mice upon intravenous inoculation. Collectively, these results demonstrate that, although MTH-Ag/PSGL-1 overexpression alone may not be sufficient for successful dissemination and organ colonization, MTH-Ag/PSGL-1 plays a critical role in hematogenous metastasis of lymphoid cancer cells.
Gas-Phase Microresonator-Based Comb Spectroscopy without an External Pump Laser (2018)

We present a novel approach to realize microresonator-comb-based high resolution spectroscopy that combines a fiber-laser cavity with a microresonator. Although the spectral resolution of a chip-based comb source is typically limited by the free spectral range (FSR) of the microresonator, we overcome this limit by tuning the 200 GHz repetition-rate comb over one FSR via control of an integrated heater. Our dual-cavity scheme allows for self-starting comb generation without the need for conventional pump-cavity detuning while achieving a spectral resolution equal to the comb line width. We measure broadband molecular absorption spectra of acetylene by interleaving 800 spectra taken at 250 MHz per spectral step using a 60 GHz coarse-resolution spectrometer and exploit advances of an integrated heater, which can locally and rapidly change the refractive index of a microresonator with low electrical consumption (0.9 GHz/mW), which is orders of magnitude lower than a fiber-based comb. This approach offers a path toward a simple, robust, and low-power consumption CMOS-compatible platform capable of remote sensing.
ChemInform Abstract: Development of a New Drug Carrier Made from Alginate. (1993)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Nonvolatile nuclear spin memory enables sensor-unlimited nanoscale spectroscopy of small spin clusters (2017)

In nanoscale metrology, dissipation of the sensor limits its performance. Strong dissipation has a negative impact on sensitivity, and sensor-target interaction even causes relaxation or dephasing of the latter. The weak dissipation of nitrogen-vacancy (NV) sensors in room temperature diamond enables detection of individual target nuclear spins, yet limits the spectral resolution of nuclear magnetic resonance (NMR) spectroscopy to several hundred Hertz, which typically prevents molecular recognition. Here, we use the NV intrinsic nuclear spin as a nonvolatile classical memory to store NMR information, while suppressing sensor back-action on the target using controlled decoupling of sensor, memory, and target. We demonstrate memory lifetimes up to 4 min and apply measurement and decoupling protocols, which exploit such memories efficiently. Our universal NV-based sensor device records single-spin NMR spectra with 13 Hz resolution at room temperature.Dissipation of the sensor is a limiting factor in metrology. Here, Pfender et al. suppress this effect employing the nuclear spin of an NV centre for robust intermediate storage of classical NMR information, allowing then to record single-spin NMR spectra with 13 Hz resolution at room temperature.
Signal-Apparition Simultaneous Source Separation for Reservoir Monitoring in the North Sea - Results from the First Field Test (2017)

Summary Signal apparition offers a new perspective on sampling of seismic data. It can be used as a fundamentally different approach to decode data acquired in a simultaneous source mode. Results from the first field test using seabed recordings in the North Sea are presented and we find that by using signal apparition principles it is possible to obtain simultaneous source separation results with very low separation errors resulting in 4D-grade separated seismic data. Our finding will have significant implications on acquisition cost and efficiency gains.
Determination of Impact Ionization Coefficients Measured from 4H Silicon Carbide Avalanche Photodiodes (2007)

Hole initiated avalanche multiplication characteristics of 4H-SiC avalanche photodiodes have been studied. The diodes had n+-n-p SiC epitaxial layers grown on a p-type substrate. These 1 mm2 devices had very low dark currents and exhibited sharp breakdown at voltages of approximately 500V. The diodes multiplication characteristics appeared to be identical when the wavelength of the illuminating light from the top varied from 288 to 325nm, implying that almost pure hole initiated multiplication was occurring. The multiplication factor data were modelled using a local multiplication model with impact ionization coefficients of 4H-SiC reported by various authors. The impact ionization coefficients extracted from submicron devices by Ng et al. were found to give accurate predictions for multiplication factors within the uncertainties of the doping levels. This result suggests that their ionization coefficients can be applied to thicker bulk 4H-SiC structures.