gebhart/patrepeval huggingface dataset:
Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity (1992)

A hypothetical mode of inhibition of protein kinase C (PKC) by the natural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a Ki of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in the development of PKC inhibitors as drugs.
Toward an Integration of IteD1-Response Theory and Cognitive Error Diagnosis (2013)

Finding the sources of misconceptions possessed by students is a difficult task because it is impossible to see what is happening in their heads. The only directly observable outcomes are the students' responses to the test items. Studying their think-aloud protocols is one method for discovering how students solve or think through problems. Several computer programs that are capable of diagnosing students' misconceptions have been developed in the past decade (Brown & Burton, 1978; Marshall, 1980; Ohlsson & Langley, 1985; Sleeman, 1984; Tatsuoka, Baillie, & Yamamoto, 1982; VanLehn, 1983). The common ground for these cognitive diagnostic systems is that they infer the unobservable cognitive processes from logical interrelationships among cognitive tasks, subtasks, and goals involved in problems representing the domain of interest. It is important that we be able to retrieve invisible things from the &quot;black box&quot; and put them into a useful form so that valuable information can be obtained for improving educational quality.
High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes (2001)

Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for monocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3-5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.
The gut as a neurological organ. (2001)

We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders.
A mouse model for poliovirus neurovirulence identifies mutations that attenuate the virus for humans (1987)

A mutation in the genome of poliovirus type 3 that is known to reduce neurovirulence in humans similarly reduces neurovirulence in mice when incorporated into a mouse-adapted-human poliovirus recombinant. Viral recombinants with a uracil at nucleotide position 472 in the 5'-noncoding regions of their genomes are unable to replicate in the mouse brain. Viral recombinants with a cytosine at this position are neurovirulent in mice. Neurovirulence of poliovirus in mice may therefore prove to be a useful indicator of the genetic stability of new attenuating mutations created by site-directed mutagenesis.
Handbook of Mathematical Functions with Formulas, Graphs, and Mathematical Tables. (1964)

A handbook of mathematical functions that is designed to provide scientific investigations with a comprehensive and self-contained summary of the mathematical functions that arise in physical and engineering problems.
Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: Results of a randomized, double-blind, placebo-controlled MR-monitored phase II trial (1997)

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.
The rise of the phoenix: the expanding role of the eosinophil in health and disease (2004)

We have entered a new phase in the evolution of our understanding of the role of the eosinophil with a greater appreciation of novel potential functions that may be ascribed to this enigmatic cell type. This review not only provides an update to our current understanding of the various immunobiological roles for the eosinophil, but also attracts attention to some novel observations predicting functions beyond its putative effector role. These observations include the intriguing possibility that the eosinophil may possess the capacity to regulate the immune and inflammatory responses in diseases such as asthma.
Characteristics of Rural Tourism Market Structure in Pearl River Delta (2012)

Some statistical data from survey are used to analyze the regional structure of tourist market and the characteristics of tourists.It is concluded that the source of tourists are geographically centralized,and the number of tourist is relatively stable.The primary tourist source markets are composed of the middle-aged and the young wage earners whose income and education levels are high.For the future development of rural tourism in Pearl River Delta,it is necessary to enhance the key market in the Pearl River Delta;to expand tourist market in the east,west and north of Guangdong,Hong Kong,Macao and Taiwan;and to exploit the potential markets in other provinces and areas.Meanwhile,attention must be paid to the development of the five key market segments which are constituted by office workers,officers,students,middle class and retired workers.
The design of a 64-bit integer multiplier/divider unit (2002)

The highlights of the design of an integer multiplier/divider unit for a 64-b processor are presented. The final design is the result of a compromise between performance, complexity, and transistor count. It is optimized for two specific operations with the same hardware being shared by the remaining operations. Thus, for example, the multiplier can be configured for the execution of several different multiply operations and its hardware is also heavily utilized in division. The divider design is optimized for repetitive division by small numbers, since this is a characteristic of several important applications planned for the processor. For such small divisors, the reciprocal is calculated and stored in a content-addressable memory. The stored reciprocals can then be used to generate quotients through fast multiplication. Simulations of the planned applications show a 20% to 30% performance increase over alternative designs.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
How I Survived the Prom Storm (2011)

Scientists are telling us that climate change will bring more extreme weather events. Well. They don't come much more extreme than the huge 22 March storm at the prom that dumped 370mm of rain in 24 hours. VNPA member Hasan Tariq was there.
Borrelia burgdorferi bind to epithelial cell proteoglycans. (1994)

Borrelia burgdorferi adhere to mammalian cells in vitro but neither the ligand(s) nor the receptor(s) has (have) been clearly established. Using an in vitro attachment-inhibition assay, a B. burgdorferi attachment mechanism has been identified. Heparin, heparan sulfate, and dermatan sulfate reduced the attachment of virulent B. burgdorferi strain 297 to HeLa cells by approximately 60%. In addition, virulent, but not avirulent, B. burgdorferi strains B31, N40, and HB19 demonstrated heparin attachment-inhibition. Attachment to Chinese hamster ovary cells deficient in heparan sulfate proteoglycans was reduced by 68% compared to attachment to wild-type cells and was identical to attachment at maximum heparin inhibition to the wild-type cells. Pretreatment of HeLa cell monolayers with heparitinase, heparinase, and chondroitinase ABC, but not with chondroitinase AC, reduced borrelial attachment by approximately 50%. A moderately high affinity, low copy number, promiscuous B. burgdorferi glycosaminoglycan receptor was demonstrated by equilibrium binding studies. A 39-kD polypeptide, purified by heparin affinity chromatography from Triton X-100 extracts derived from virulent borrelia, was a candidate for this receptor. These studies indicate that one mode of B. burgdorferi attachment to eukaryotic cells is mediated by a borrelial glycosaminoglycan receptor attaching to surface-exposed proteoglycans on mammalian cells.
Identifying spots in microarray images (2002)

Microarray technology has provided a way to quantitate the simultaneous expression of a large number of genes. This approach is dependent on reproducible, accurate identification and quantitation of spot intensities. In this paper, clustering-based image segmentation is described to extract the target intensity of the microarray spots. While the technique is generic, its effectiveness on extracting spot intensities on arrays obtained from a two-color (Cy3/Cy5) experiment is discussed. The approximate boundaries of the spots are determined initially by manual alignment of rectangular grids. The pixel intensities of the image (I) inside a grid, is mapped onto a one-dimensional vector (v). The k-means clustering technique is applied to generate a binary partition of v. The median value of the pixel intensities inside each of the clusters for a given spot determines its foreground and the local background intensity. The difference in the median value of the foreground and the background intensity is the desired target intensity of the spot. The results are compared against those obtained using a region growing approach.
Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death (1995)

The low-affinity receptor for leukemia inhibitory factor (LIFR) interacts with gp130 to induce an intracellular signal cascade. The LIFR-gp130 heterodimer is implicated in the function of diverse systems. Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth.
Applications of vibrational spectroscopy in pharmaceutical research and development (2007)

Part One: Introduction Introduction to Vibrational Spectroscopy Peter R. Griffiths Part Two: Drug Discovery Sampling Techniques and Fiber-Optic Probes John M. Chalmers and Peter R. Griffiths Vibrational Spectroscopy in the Discovery Phase Component of Pharmaceutical Research Don E. Pivonka Applications of Vibrational Spectroscopy to Combinatorial Chemistry Don E. Pivonka Vibrational Spectroscopic Analysis for the Determination of Structure-Activity Relationships (SARs) in Molecular Binding Don E. Pivonka and Isao Noda Applications of Vibrational Optical Activity in the Pharmaceutical Industry Laurence A. Nafie and Rina K. Dukor Characterization and Optimization of Chemical Synthesis Using Real-Time Vibrational Spectroscopy Fadi Homsi, Paul Barrett, Jian Wang and Roel Ferwerda Part Three: Drug Development Infrared and Raman Spectroscopy for Process Development George Zhou, Robert Guenard and Zhihong Ge The Analysis of Pharmaceutical Substances and Formulated Products by Vibrational Spectroscopy Don Clark and Alexander Pysik Raman Analysis of Pharmaceuticals David E. Bugay, Jan-Olav Henck, Michael L. Longmire and Fiona C. Thorley Vibrational Spectroscopy of Solid-State Forms - Introduction, Principles and Overview Terry L. Threlfall and John M. Chalmers Vibrational Spectroscopy of Solid-State Forms - Applications and Examples David H. Igo and Pingyun Chen Pharmaceutical Applications of Chemical Mapping and Imaging Don Clark, Mark Henson, Fred LaPlant, Slobodan Sasic and Lin Zhang Terahertz Spectroscopy for Pharmaceutical Applications Mike Claybourn, Husheng Yang, Lubomir Gradinarsky, Jonas Johansson and Staffan Folestad Part Four: Conclusions History, Trends and Prognostications Peter R. Griffiths, John M. Chalmers and Don E. Pivonka
Void free and low stress shallow trench isolation technology using P-SOG for sub 0.1 μm device (2003)

Highly reliable void free shallow trench isolation (VF-STI) technology by employing polysilazane based inorganic spin-on-glass (P-SOG) is developed for sub-0.1 /spl mu/m devices. In order to overcome the difficulties from the gap-filling and accumulated mechanical stress in STI, a P-SOG pillar is introduced at the trench bottom. As a result, the P-SOG pillar, having low stress, improves data retention time and hot carrier immunity in 256 Mbit DRAM by reducing cumulative STI stress. In addition, VF-STI shows an excellent extendibility in terms of gap filling capability even at an aspect ratio of more than 10 without void formation.
Discovery of Amide (Peptide) Bond Synthetic Activity in Acyl-CoA Synthetase (2008)

Acyl-CoA synthetase, which is one of the acid-thiol ligases (EC 6.2.1), plays key roles in metabolic and regulatory processes. This enzyme forms a carbon-sulfur bond in the presence of ATP and Mg(2+), yielding acyl-CoA thioesters from the corresponding free acids and CoA. This enzyme belongs to the superfamily of adenylate-forming enzymes, whose three-dimensional structures are analogous to one another. We here discovered a new reaction while studying the short-chain acyl-CoA synthetase that we recently reported (Hashimoto, Y., Hosaka, H., Oinuma, K., Goda, M., Higashibata, H., and Kobayashi, M. (2005) J. Biol. Chem. 280, 8660-8667). When l-cysteine was used as a substrate instead of CoA, N-acyl-l-cysteine was surprisingly detected as a reaction product. This finding demonstrated that the enzyme formed a carbon-nitrogen bond (EC 6.3.1 acid-ammonia (or amide) ligase (amide synthase); EC 6.3.2 acid-amino acid ligase (peptide synthase)) comprising the amino group of the cysteine and the carboxyl group of the acid. N-Acyl-d-cysteine, N-acyl-dl-homocysteine, and N-acyl-l-cysteine methyl ester were also synthesized from the corresponding cysteine analog substrates by the enzyme. Furthermore, this unexpected enzyme activity was also observed for acetyl-CoA synthetase and firefly luciferase, indicating the generality of the new reaction in the superfamily of adenylate-forming enzymes.
Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice (1999)

The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4(+) T cells targeting virally infected central nervous system-resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope-specific CD4(+) T cells via epitope spreading. Here we show that F4/80(+), I-A(s+), CD45(+) macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell-mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.
The C Terminus of the Escherichia coli RecA Protein Modulates the DNA Binding Competition with Single-stranded DNA-binding Protein (2003)

The nucleation step of Escherichia coli RecA filament formation on single-stranded DNA (ssDNA) is strongly inhibited by prebound E. coli ssDNA-binding protein (SSB). The capacity of RecA protein to displace SSB is dramatically enhanced in RecA proteins with C-terminal deletions. The displacement of SSB by RecA protein is progressively improved when 6, 13, and 17 C-terminal amino acids are removed from the RecA protein relative to the full-length protein. The C-terminal deletion mutants also more readily displace yeast replication protein A than does the full-length protein. Thus, the RecA protein has an inherent and robust capacity to displace SSB from ssDNA. However, the displacement function is suppressed by the RecA C terminus, providing another example of a RecA activity with C-terminal modulation. RecADeltaC17 also has an enhanced capacity relative to wild-type RecA protein to bind ssDNA containing secondary structure. Added Mg(2+) enhances the ability of wild-type RecA and the RecA C-terminal deletion mutants to compete with SSB and replication protein A. The overall binding of RecADeltaC17 mutant protein to linear ssDNA is increased further by the mutation E38K, previously shown to enhance SSB displacement from ssDNA. The double mutant RecADeltaC17/E38K displaces SSB somewhat better than either individual mutant protein under some conditions and exhibits a higher steady-state level of binding to linear ssDNA under all conditions.
Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation (2013)

Advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) have a pathogenetic role in the development and progression of different oxidative-based diseases including diabetes, atherosclerosis, and neurological disorders. AGEs and ALEs represent a quite complex class of compounds that are formed by different mechanisms, by heterogeneous precursors and that can be formed either exogenously or endogenously. There is a wide interest in AGEs and ALEs involving different aspects of research which are essentially focused on set-up and application of analytical strategies (1) to identify, characterize, and quantify AGEs and ALEs in different pathophysiological conditions; (2) to elucidate the molecular basis of their biological effects; and (3) to discover compounds able to inhibit AGEs/ALEs damaging effects not only as biological tools aimed at validating AGEs/ALEs as drug target, but also as promising drugs. All the above-mentioned research stages require a clear picture of the chemical formation of AGEs/ALEs but this is not simple, due to the complex and heterogeneous pathways, involving different precursors and mechanisms. In view of this intricate scenario, the aim of the present review is to group the main AGEs and ALEs and to describe, for each of them, the precursors and mechanisms of formation.