gebhart/patrepeval huggingface dataset:
Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer's Disease. (2017)

Neflamapimod (previously code named VX-745) is a clinical phase 2b-ready highly specific inhibitor of the intra-cellular enzyme p38 mitogen activated protein kinase alpha ("p38α") that is being developed as a disease-modifying drug for Alzheimer's disease (AD) that acts via targeting synaptic dysfunction. Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and developed previously by Vertex through to phase 2a in rheumatoid arthritis. EIP Pharma licensed the compound in 2014 for development and commercialization as a treatment of central nervous system (CNS) disorders. Neflamapimod is the most advanced in the clinic drug that targets specific molecular mechanisms within neurons that leads to synaptic dysfunction, the pathogenic process that is now considered to be a major driver of the development of memory deficits and disease progression in the early stages of AD. Based on the scientific rationale of targeting synaptic dysfunction and the preclinical data, neflamapimod has the potential to both reverse memory deficits and slow disease progression. Phase 2a clinical data in patients with early-stage AD (MMSE 20-28, biomarker positive) provides evidence that the preclinical science may be translatable to human Alzheimer's, as 6- to 12-weeks of neflamapimod treatment led to significant improvement in episodic memory, the best clinical measure of synaptic dysfunction in AD. A phase 2b six-month placebo-controlled 150-patient clinical study is anticipated to start by end of 2017. This study is designed to definitively demonstrate that neflamapimod reverses memory deficits, and also to provide preliminary evidence that the drug slows disease progression.
Activity of &#947; -Secretase on Substrates Other than APP (2008)

Gamma-secretase is an intramembranous protein complex that cleaves many type-I membrane proteins, including the Notch receptor and the beta-amyloid precursor protein (APP). Interest in gamma-secretase comes, in part, from the fact that this multiprotein complex is responsible for the cleavage of APP that generates the amyloid-beta peptide (Abeta), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, molecular identification of the complex has shown that gamma-secretase is an aspartyl protease composed of four different members that are essential for the enzymatic activity: presenilin 1, aph1, pen-2 and nicastrin. In recent years, an increasing number of type-I membrane proteins have been shown to be cleaved by gamma-secretase. How the enzyme cleaves such a set of substrates with diverse functions and subcellular localizations is not well understood. In overexpression assays, the gamma-secretase cleavage of some substrates releases intracellular domains with signaling properties. On the other hand, the loose specificity required for intramembrane cleavage has raised the possibility of gamma-secretase as the membrane proteasome. The impact of gamma-secretase on other substrates has clear implications for the development of new therapies for AD, and in particular for the search of gamma-secretase inhibitors or modulators. Interference with the cleavage of some of the gamma-secretase substrates has been shown to be associated with serious adverse effects in animal models. The understanding of the mechanism by which gamma-secretase recognizes and cleaves all these proteins is of great importance to clarify the function of gamma-secretase and its role as a therapeutic target in AD, and possibly in other diseases in which gamma-secretase is involved.
DOES ACID RAIN INCREASE HUMAN EXPOSURE TO MERCURY? A REVIEW AND ANALYSIS OF RECENT LITERATURE (1995)

The literature suggests that acid deposition may lead to increased mercury (Hg) contamination of fish. Employing published empirical relationships, we have estimated the change in associated Hg contamination with an increase in sulphate deposition from 0.25 to 1.25 g sulfur/m2/year. In seepage lakes, one can predict that Hg in walleye from these lakes, and subsequent human exposure due to consumption of these fish, would be elevated at the higher rate of sulphate deposition. However, for drainage lakes, increasing acidic deposition was predicted to reduce Hg accumulation in lake trout and northern pike. Subsequent human exposure to Hg due to consumption of these species from drainage lakes was therefore also predicted to be lower at the higher rate of acidic deposition. We concluded that the hypothesis that acidic deposition increases mercury (Hg) contamination in fish, and thereby mercury exposure in humans via fish consumption, is only true for acidic deposition onto seepage lakes.
Abstract 3885: FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer. (2013)

Abstract Metastatic breast cancer is a principle cause of female mortality. In general, metastatic cancers show poor response to current treatments and therefore the development of new therapies is essential. Metastasis is a multi-step process where cancer cells migrate from the primary tumour to other distant organs. For this to occur, degradation of the extracellular matrix is required, allowing cancer cells to invade the vasculature and migrate to distant sites. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that breakdown the extracellular matrix, with increased expression of MMP-2 and -9 associated with metastatic breast cancer. MMP activity is tightly regulated by the tissue inhibitors of metalloproteinases (TIMPs): TIMP-1 inhibits MMP-9 activity while TIMP-2 inhibits MMP-2 activity. Studies have shown that the nuclear receptor Farnesoid X-receptor (FXR) is involved in regulation of MMP and TIMP activity in hepatic and vascular tissues. As FXR is highly expressed in metastatic breast cancer, the aim of the current study was to investigate whether FXR is a novel regulator of MMP-2 and -9 in breast cancer cells. The viability of the breast cancer cell lines MCF7 (Estrogen receptor positive) and MDA-MB-468 (Estrogen receptor negative) was measured after exposure to the FXR agonists chenodeoxycholic acid (CDCA) and 3-[2-[2-Chloro-4-[[3-(2, 6-dichlorophenyl)-5-(1-methylethyl)-4 isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064). In both cases, these FXR ligands caused cell death in both cell lines, with reduction of cell viability being significantly higher in the triple negative MDA-MB-468 cells. mRNA and protein levels of MMP-2 and -9 within both cell lines did not change after FXR activation, as measured by real time PCR and Western blotting. However, GW4064 did increase secreted MMP activity, as measured by a fluorescent substrate, in a concentration dependent manner, whereas CDCA had no effect. Such data suggests that while FXR ligands may be cytotoxic to breast cancer cells, they may also increase the risk of invasion and metastasis. Citation Format: Noura Alasmael, Lisiane B. Meira, Karen Swales, Nick Plant. FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3885. doi:10.1158/1538-7445.AM2013-3885
Studies in polymerization XIV. The solid-state polymerization of acrylic and methacrylic acids (1963)

Abstract Crystalline acrylic and methacrylic acids can be polymerized by ultra-violet irradiation a t temperatures not far removed from their melting points. In both cases the reaction proceeds in such a way as to give non-crystalline and disoriented polymer. Irradiation of methacrylic acid under these conditions gives a measurable free radical concentration, whereas no free radicals are detectable by electron spin resonance in irradiated acrylic acid. The production of observable free radicals in methacrylic acid crystals is very temperature dependent, decreasing with reduction in temperature. The polymerizations have been studied in some detail by observing the changes in the optical retardation of thin single crystals while undergoing reaction. In this way a post-irradiation reaction was observed with methacrylic acid but not with acrylic acid samples. The most striking observations were those obtained when the crystals were subjected to small mechanical compressive stresses, when the polymerization reaction was generally retarded or stopped. To account for the results obtained it is suggested that the polymerization reaction takes place in association with crystal dislocations. The effect of mechanical stress is considered to arise from the displacement of dislocations. Two possible mechanisms, depending on the properties of crystal dislocations, have been suggested. Although more experimental data are required it is thought that the observed pressure effect will be of considerable importance in the elucidation of the details of the polymerization.
Objective video quality metrics (2007)

This paper discusses methods used in different objective video quality metrics. An experimental comparison of different objective methods is also conducted. This experiment shows the importance of video content for a subjective quality evaluation not comprised well by the objective metrics used.
Neurophysiological assessment of perceived image quality using steady-state visual evoked potentials (2015)

An approach to the neural measurement of perceived image quality using electroencephalography (EEG) is presented. 6 different images were tested on 6 different distortion levels. The distortions were introduced by a hybrid video encoder. The presented study consists of two parts: In a first part, subjects were asked to evaluate the quality of the test stimuli behaviorally during a conventional psychophysical test using a degradation category rating procedure. In a second part, subjects were presented undistorted and distorted texture images in a periodically alternating fashion at a fixed frequency. This alternating presentation elicits so called steady-state visual evoked potentials (SSVEP) as a brain response that can be measured on the scalp. The amplitude of modulations in the brain signals is significantly and strongly negatively correlated with the magnitude of visual impairment reported by the subjects. This neurophysiological approach to image quality assessment may potentially lead to a more objective evaluation, as behavioral approaches suffer from drawbacks such as biases, inter-subject variances and limitations to test duration.
Digital Signature Based on ECDLP (2010)

In this paper, Digital Signature Schemes (DSS) have been proposed. The schemes are based on Elliptic Curve Discrete Logarithm Problem (ECDLP). The schemes utilize the inherent advantage of Elliptic Curve Cryptosystem in terms of smaller key size and lower computational overhead to its counterpart public cryptosystems such as RSA and ElGamal. The schemes have been proved to be robust, untraceable and correct.
Improved CT image quality using a new fully physical imaging chain (2010)

This paper describes the image quality improvements achieved by developing a new fully physical imaging chain. The key enablers for this imaging chain are a new scatter correction technique and an analytic computation of the beam hardening correction for each detector. The new scatter correction technique uses off-line Monte Carlo simulations to compute a large database of scatter kernels representative of a large variety of patient shapes and an on-line combination of those based on the attenuation profile of the patient in the measured projections. In addition, profiles of scatter originating from the wedge are estimated and subtracted. The beam hardening coefficients are computed using analytic simulations of the full beam path of each individual ray through the scanner. Due to the new approach, scatter and beam hardening are computed from first principles with no further tuning factors, and are thus straight forward to adapt to any patient and scan geometry. Using the new fully physical imaging chain unprecedented image quality was achieved. This is demonstrated with a special scatter phantom. With current image correction techniques this phantom typically shows position dependent inhomogeneity and streak artifacts resulting from the impact of scattered radiation. With the new imaging chain these artifacts are almost completely eliminated, independent of position and scanning mode (kV). Further preliminary patient studies show that in addition to fully guaranteeing an absolute Hounsfield scale in arbitrary imaging conditions, the new technique also strongly sharpens object boundaries such as the edges of the liver.
Electronic Population Inversion in HCCO/DCCO Products from Hyperthermal Collisions of O(<sup>3</sup>P) with HCCH/DCCD (2013)

The dynamics of hyperthermal O((3)P) reactions with acetylene have been investigated with the use of crossed molecular beams techniques, employing both mass spectrometric and optical detection of products. With collision energies of 40-150 kcal mol(-1), O((3)P) + HCCH/DCCD → HCCO/DCCO + H/D may follow multiple pathways to form the ketenyl radical (HCCO or DCCO) in ground doublet states or in electronically excited quartet and doublet states. Theoretical calculations support the assignment of the various reaction pathways. The fraction of electronic excitation is substantial. At the highest collision energy studied, ∼65% of the ketenyl radical products that survive are electronically excited, with the majority of the excited products in a quartet state. In this case, a population inversion exists between the electronically excited quartet and ground doublet states of the ketenyl product. Such significant electronic excitation in products is unusual in bimolecular reactions, especially when ground-state products are accessible by spin-allowed pathways.
The potentials of in-situ-projection for augmented workplaces in production (2013)

Interactive projections have been around for more than a decade. We measured their potentials for augmented workplaces in production. For this purpose we built the prototype of an assistive system projecting instructions directly into the workspace (in situ). While it can be applied in every production environment, the system was first implemented and tested where it is needed the most: in a sheltered work organization employing persons with impairments.
579. Synthesis of bis-[p-di-(2-chloroethyl)aminophenoxy]alkanes (1959)

F. Bergel and E. Reiner, J. Chem. Soc., 1959, 2890 DOI: 10.1039/JR9590002890
Mononuclear Silver Complexes for Efficient Solution and Vacuum‐Processed OLEDs (2018)

Abstract Carbene metal amides are a new class of highly efficient light‐emitting molecules based on a linear donor–metal–acceptor geometry. Here the synthesis, structure, and photo‐ and electroluminescence of carbene silver carbazolato complexes, ( Ad L)Ag(Cz) [ Ad L = adamantyl‐substituted cyclic (alkyl)(amino)carbene; Cz = carbazolate ( 1 ) and 3,6‐ t Bu 2 Cz ( 2 )], are reported. They display green emission with photoluminescence quantum yields of up to 74%. Efficient mixing of triplet and singlet excited states is observed, with sub‐microsecond thermally activated radiative triplet lifetimes. These complexes provide prototype organic light‐emitting diodes based exclusively on silver emitters, with external quantum efficiencies of up to 14%.
Roof Age Determination for the Automated Site-Selection of Rooftop Solar (2020)

Rooftop solar is one of the most promising tools for drawing down greenhouse gas (GHG) emissions and is cost-competitive with fossil fuels in many areas of the world today. One of the most important criteria for determining the suitability of a building for rooftop solar is the current age of its roof. The reason for this is simple -- because rooftop solar installations are long-lived, the roof needs to be new enough to last for the lifetime of the solar array or old enough to justify being replaced. In this paper we present a data-driven method for determining the age of a roof from historical satellite imagery, which removes one of the last obstacles to a fully automated pipeline for rooftop solar site selection. We estimate that a full solution to this problem would reduce customer acquisition costs for rooftop solar by $\sim$20\%, leading to an additional $\sim$750 megatons of CO$_2$ displaced between 2020 and 2050.
EXPRESSION IN MAMMALIAN CELLS OF FUSION PROTEINS BETWEEN HUMAN FACTORS IX AND VII (1987)

The vitamin K-dependent plasma proteins demonstrate remarkable similarities in their structures: all have multiple domains in common and extensive homology is observed within many of these domains. In order to investigate the structure-function relationship of these proteins, we have interchanged domains of one protein (factor IX) with that of another (factor VII) and have compared the expression of these fusion proteins with recombinant and native factors IX and VII. Oligonucleotide-directed mutagenesis was used to generate four fusion proteins: factor IX/VII-1, which contains the factor IX leader and gla domain fused to the growth factor and serine protease of factor VII; factor VII/IX-1, a reciprocal fusion protein of factor IX/VII-1; factor IX/VII-2, which contains the factor IX leader adjoined to the mature factor VII protein sequence; and factor VII/IX-2, the reciprocal fusion protein of factor IX/VII-2. The cDNAs encoding all four proteins were cloned into mammalian expression vectors, and to date three of these (factors IX/VII-1, 2 and VII/IX-1) have been transfected into baby hamster kidney (BHK) cells or 293 cells and characterized. Factors IX/VII-1 and VII/IX-1 were both secreted at levels comparable to recombinant factors IX and VII. The factor IX/VII-1 was identical in molecular weight to native or recombinant factor VII (i.e., 53 K). Factor VII/IX-1 was expressed as two proteins with molecular weights around 68 kd, as observed with recombinant factor IX. The factor IX/VII-1 protein has been purified to homogeneity and has been found to possess factor VII biological activity, but at a specific activity approximately 20% that of plasma factor VII. Thus, the gla domain of one clotting factor is capable of directing the activation of another and of generating biologically active protein. In contrast, no activity was observed with the factor IX/VII-2 fusion protein, indicating that there are limits to the interchanges which can generate functional blood clotting factors.
Pallister-Hall syndrome phenotype in mice mutant for Gli3 (2002)

Mutations in the GLI3 gene have been identified in several human malformation syndromes. One of these autosomal dominant developmental disorders is Pallister-Hall syndrome (PHS; MIM146510), which is associated with central polydactyly and other malformations. Interestingly, the mutations in the GLI3 transcription factor gene identified in patients with PHS are restricted to the region 3' of the zinc finger-encoding domain, leaving this DNA-binding domain intact. We have investigated the consequences of this mutation on the development of multiple organ systems by introducing a targeted mutation in mice. We found that mice homozygous for the mutation showed a central polydactyly, thus modeling one of the major abnormalities of the human syndrome. Moreover, Gli3-mutant mice displayed a wide range of developmental abnormalities encompassing almost all of the common PHS features, including imperforate anus, gastrointestinal, epiglottis and larynx defects, abnormal kidney development, and absence of adrenal glands. Thus, our Gli3-mutant mice provide an excellent model for studies of both the pathogenesis of PHS and Gli3 functions in the development of the affected organ systems.
Natural population analysis (1985)

A method of ‘‘natural population analysis’’ has been developed to calculate atomic charges and orbital populations of molecular wave functions in general atomic orbital basis sets. The natural analysis is an alternative to conventional Mulliken population analysis, and seems to exhibit improved numerical stability and to better describe the electron distribution in compounds of high ionic character, such as those containing metal atoms. We calculated ab initio SCF-MO wave functions for compounds of type CH3X and LiX (X=F, OH, NH2, CH3, BH2, BeH, Li, H) in a variety of basis sets to illustrate the generality of the method, and to compare the natural populations with results of Mulliken analysis, density integration, and empirical measures of ionic character. Natural populations are found to give a satisfactory description of these molecules, providing a unified treatment of covalent and extreme ionic limits at modest computational cost.
Toward a method of object-oriented concurrent programming (1993)

PROGRAMMING hile there have been many attempts to provide objectoriented languages with a model of concurrency, few have dealt with reusability and methodology. Here we propose a concurrent model that takes into account such important concerns. Concept unifications are a necessity, and underlie the need to make object-oriented programming adaptable to concurrency. The model characteristics, especially reusability, permit definition of a concurrent object-oriented design method. The model, which makes extensive use of objectoriented techniques such as inheritance and polymorphism, is presented followed by development of the concurrent programming method. A real-time example of an automotive cruise control system illustrates and exercises the method.
<i>PRKX</i>, <i>TTBK2</i> and <i>RSK4</i> expression causes sunitinib resistance in kidney carcinoma‐ and melanoma‐cell lines (2011)

Resistance to chemotherapeutic agents constitutes a major problem in the treatment of cancer. Over the past years, multi-targeted protein kinase inhibitors such as Gleevec, Sunitinib and Sorafenib are gaining wider acceptance for cancer treatment. These drugs show anti-tumor activity in vitro and in patients. Extended usage of these drugs in therapy commonly results in disease progression due to formation of resistance caused by rearrangements and accumulation of mutations in the unstable cancer cell genome. However, the underlying drug-specific mechanisms for the development of resistance remain elusive. Hence, a detailed understanding of the molecular genetic events involved in this processes is pivotal to counteract are not directly targeted by Sunitinib (unpublished data). Therefore, development of specific or multi-targeted inhibitors for these kinases for combinatorial therapy with e.g., an IL-8 neutralizing antibody might circumvent or substantially delay Sunitinib resistance formation and enhance survival prognosis. PRKX, TTBK2 and RSK4 expression. The specific reduction of these genes employing siRNA was sufficient to sensitize the kidney- and melanoma-cell lines against Sunitinib. In line with the elevated expression of PRKX, TTBK2 or RSK4, this sensitization effect was strikingly higher in the Sunitinib resistant cell lines, suggesting an expression-based mechanism of these genes to trigger Sunitinib resistance. Hence, we propose that PRKX, TTBK2 and RSK4 are potential resistance markers in Sunitinib therapy and might therefore represent targets for the development of novel strategies to overcome resistance.