gebhart/patrepeval huggingface dataset:
Vemurafenib Potently Induces Endoplasmic Reticulum Stress–Mediated Apoptosis in BRAFV600E Melanoma Cells (2013)

The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2α (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.
Evolution of the C 30 Carotenoid Synthase CrtM for Function in a C 40 Pathway (2002)

The C30 carotene synthase CrtM from Staphylococcus aureus and the C40 carotene synthase CrtB from Erwinia uredovora were swapped into their respective foreign C40 and C30 biosynthetic pathways (heterologously expressed in Escherichia coli) and evaluated for function. Each displayed negligible ability to synthesize the natural carotenoid product of the other. After one round of mutagenesis and screening, we isolated 116 variants of CrtM able to synthesize C40 carotenoids. In contrast, we failed to find a single variant of CrtB with detectable C30 activity. Subsequent analysis revealed that the best CrtM mutants performed comparably to CrtB in an in vivo C40 pathway. These mutants showed significant variation in performance in their original C30 pathway, indicating the emergence of enzymes with broadened substrate specificity as well as those with shifted specificity. We discovered that Phe 26 alone determines the specificity of CrtM. The plasticity of CrtM with respect to its substrate and product range highlights the potential for creating further new carotenoid backbone structures.
Engineering the ABA Plant Stress Pathway for Regulation of Induced Proximity (2011)

Chemically induced proximity (CIP) systems use small molecules and engineered proteins to control and study biological processes. However, small molecule-based systems for controlling protein abundance or activities have been limited by toxicity, instability, cost, and slow clearance of the small molecules in vivo. To address these problems, we modified proteins of the plant abscisic acid (ABA) stress response pathway to control the proximity of cellular proteins and showed that the system could be used to regulate transcription, signal transduction, and subcellular localization of proteins in response to exogenously applied ABA. We also showed that the ABA CIP system can be combined with other CIP systems to simultaneously control multiple processes. We found that, when given to mice, ABA was orally available and had a 4-hour half-life. These properties, along with its lack of toxicity and low cost, suggest that ABA may be well suited for therapeutic applications and as an experimental tool to control diverse cellular activities in vivo.
Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. (1992)

As a common characteristic of tumor cells, as well as of normal proliferating cells in the G1-phase of cell cycle, one finds constitutive high levels of all the glycolytic metabolites arising between glucose 6-phosphate and phosphoenolpyruvate. Thus, it is that the phosphometabolites fructose 1,6-bisphosphate, ribose 5-P, P-ribose-PP, NAD, GTP, CTO, UTP, UDP-glucose, glycerol 3-P, glycerol phosphocholine and glycerol phosphoethanolamine are useful in the 31P-nuclear magnetic resonance (NMR) detection of solid tumors in animals and man. This expansion of phosphometabolites is achieved during tumor formation as a result of reductions in levels of enzymes degrading phosphometabolites, owing to the decline in the glycerol 3-P hydrogen shuttle, and as a consequence of alterations in the glycolytic isoenzyme equipment. Tumor cells typically express a particular isoenzyme of pyruvate kinase called type M2 (K) at high levels. This isoenzyme is subject to a complex regulation by amino acids, by fructose 1,6-bisphosphate, and by hormonal- and oncogene-dependent phosphorylation. Pyruvate kinase type M2 is a substrate for the oncogene encoded PP60v-src-tyrosine kinase. A drastic decrease in the affinity for its substrate phosphoenolpyruvate found after transformation by the src-oncogene can be explained as a consequence of the phosphorylation of pyruvate kinase in serine and tyrosine. These phosphorylations induce the breakdown of tetrameric pyruvate kinase to the trimeric and dimeric forms. Unlike the tetrameric form, the dimeric form as a low affinity for phosphoenolpyruvate. Partial inactivation of pyruvate kinase and enolase on the one hand, and a hyperactivation of hexokinase and phosphofructokinase on the other hand, lead to an expansion of all metabolites. Only when these metabolites attain high levels, thereby assuring a sufficient supply of metabolites for RNA, DNA, lipid, and complex carbohydrate synthesis, can cell proliferation proceed. This accumulation of metabolites in the G1-phase cells has been termed a "metabolic budget system" because it senses not only the actual nutrient levels, but also the supply over a period of time. Monoclonal antibodies specific for the dimeric form of pyruvate kinase type M2 can be used for the immunohistological detection of tumor cells. The amount of the dimeric form in tumor cells closely correlates with the degree of malignancy and can be used for a nonspecific detection of tumors based on assays performed with patient's plasma.
Modulation of peptide binding to specific receptors on rat pituitary cells by tumor-promoting phorbol esters: decreased binding of thyrotropin-releasing hormone and somatostatin as well as epidermal growth factor. (1982)

Phorbol esters increase prolactin synthesis and release and inhibit growth hormone production by GH4C1 cells, a clonal strain of rat pituitary cells. We examined the actions of phorbol esters on the binding of peptides that regulate the function of GH4C1 cells and found that phorbol esters decreased the specific binding of epidermal growth factor (EGF), thyrotropinreleasing hormone (TRH), and somatostatin. 12- O -Tetradecanoyl-13-phorbol acetate (TPA) at 100 ng/ml decreased 125I-EGF binding to 15% of control within 1 hr, 3H-TRH binding to 30% of control after 4 hr, and 125I-Tyr1-somatostatin binding to 40% of control after 24 hr. The action of TPA on 125I-EGF and 3H-TRH binding was temperature dependent, occurring at 37° but not at 4°, and was reversed within 72 hr after removal of TPA. By Scatchard analysis of 125I-EGF-binding data, TPA (100 ng/ml) decreased the concentration dependence of 125I-EGF binding (7- to 10-fold) when binding was assayed at 37° and decreased both the apparent affinity (2- to 6-fold) and the number of 125I-EGF-binding sites (by 25 to 50%) when binding was assayed at 4°. The decrease in 3H-TRH binding induced by TPA (100 ng/ml) was due to a 2- to 5-fold decrease in the apparent affinity of binding at 37°. Thus, unlike findings reported for certain other cell lines, phorbol esters induce an alteration in membrane function in GH4C1 cells which decreases the binding to specific receptors for more than one regulatory peptide. Modulation of receptors for regulatory ligands may play a role in the mechanism by which phorbol esters promote neoplastic transformation, but the action on “growth factor” receptors cannot be considered specific in all cell types.
Paired‐pulse magnetic stimulation of the human motor cortex: differences among I waves (1998)

1. In paired-pulse cortical stimulation experiments, conditioning subthreshold stimuli suppress the electromyographic (EMG) responses of relaxed muscles to suprathreshold magnetic test stimuli at short interstimulus intervals (ISIs) (1-5 ms) and facilitate them at long ISIs (8-15 ms). 2. We made paired-pulse magnetic stimulation studies on the response of the first dorsal interosseous muscle (FDI) produced by I1 or I3 waves using our previously reported method which preferentially elicits one group of I waves when subjects make a slight voluntary contraction. In some experiments the conditioning and test stimuli were oppositely directed, in the others they were oriented in the same direction. Single motor unit responses were recorded with a concentric needle electrode, and surface EMG responses with cup electrodes. 3. In post-stimulus time histograms (PSTHs) of the firing probability of motor units, the peaks produced by I3 waves were decreased by a subthreshold conditioning stimulus that preferentially elicited I1 or I3 waves at an ISI of 4 ms. The amount of decrement depended on the intensity of the conditioning stimulus. The stronger the conditioning stimulus, the greater the suppression. In contrast, the peaks produced by I1 waves were little affected by any type of subthreshold conditioning stimulus, given 4 ms prior to the test stimulus. At an ISI of 10 ms, a subthreshold conditioning stimulus slightly decreased the size of the peak produced by the I3 waves, but did not affect the peaks evoked by I1 waves. 4. Surface EMGs showed that a subthreshold conditioning stimulus suppressed the responses produced by I3 waves irrespective of its current direction (anterior or posterior). Both the amount and duration of suppression depended on the intensity of the conditioning stimulus, but not on its current direction. Both parameters increased when the intensity increased. At a high intensity conditioning stimulus, suppression was evoked at ISIs of 1-20 ms, compatible with the duration of GABA-mediated inhibition found in animal experiments. Responses produced by I1 waves were little affected by any type of subthreshold conditioning stimulus. 5. We conclude that a subthreshold conditioning stimulus given over the motor cortex moderately suppresses I3 waves but does not affect I1 waves. The duration of suppression of the I3 waves supports the idea that this is an effect of GABAergic inhibition within the motor cortex.
Topical Retinaldehyde with Glycolic Acid: Study of Tolerance and Acceptability in Association with Anti-Acne Treatments in 1,709 Patients (2005)

These data show that a combination of RAL 0.1% and glycolic acid 6% may be used in association with other topical anti-acne treatments (benzoyl peroxide and topical antibiotics) with an excellent tolerance.
Remarkable transglycosylation activity of glycosynthase mutants of Endo-D, an endo-β-N-acetylglucosaminidase from Streptococcus pneumoniae. (2012)

VOLUME 287 (2012) PAGES 11272–11281 Throughout the article, some of the Asn-322 mutants were mistakenly typed as Asn-332 mutants. All instances of “N332A” or “N332Q” should be corrected as “N322A” or “N322Q” mutant.
Approaches to Text Retreival for Structured Documents (1990)

Documents such as textbooks, dictionaries, and encyclopedias are inherently structured, in the sense that they are meant to be used selectively by skipping from section to section instead of reading sequentially from one end to the other. Experiments are described to provide selective reading lists for textbook materials in answer to questions submitted by the user population. A textbook in information science is used for experimental purposes.
Chemical combination effects predict connectivity in biological systems (2007)

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured.
Preparation and Molecular and Electronic Structures of Iron(0) Dinitrogen and Silane Complexes and Their Application to Catalytic Hydrogenation and Hydrosilation (2004)

Reduction of the five-coordinate iron(II) dihalide complexes (iPrPDI)FeX2 (iPrPDI = ((2,6-CHMe2)2C6H3N=CMe)2C5H3N; X = Cl, Br) with sodium amalgam under 1 atm of dinitrogen afforded the square pyramidal, high spin iron(0) bis(dinitrogen) complex (iPrPDI)Fe(N2)2. In solution, (iPrPDI)Fe(N2)2 loses 1 equiv of N2 to afford the mono(dinitrogen) adduct (iPrPDI)Fe(N2). Both dinitrogen compounds serve as effective precatalysts for the hydrogenation and hydrosilation of olefins and alkynes. Effecient catalytic reactions are observed with low catalyst loadings (< or = 0.3 mol %) at ambient temperature in nonpolar media. The catalytic hydrosilations are selective in forming the anti-Markovnikov product. Structural characterization of a high spin iron(0) alkyne and a bis(silane) sigma-complex has also been accomplished and in combination with isotopic labeling studies provides insight into the mechanism of both catalytic C-H and catalytic C-Si bond formation.
Probability of error calculation of OFDM systems with frequency offset (2001)

Orthogonal frequency-division multiplexing (OFDM) is sensitive to the carrier frequency offset (CFO), which destroys orthogonality and causes intercarrier interference (ICI), Previously, two methods were available for the analysis of the resultant degradation in performance. Firstly, the statistical average of the ICI could be used as a performance measure. Secondly, the bit error rate (BER) caused by CFO could be approximated by assuming the ICI to be Gaussian. However, a more precise analysis of the performance (i.e., BER or SER) degradation is desirable. In this letter, we propose a precise numerical technique for calculating the effect of the CFO on the BER or symbol error in an OFDM system. The subcarriers can be modulated with binary phase shift keying (BPSK), quaternary phase shift keying (QPSK), or 16-ary quadrature amplitude modulation (16-QAM), used in many OFDM applications. The BPSK case is solved using a series due to Beaulieu (1990). For the QPSK and 16-QAM cases, we use an infinite series expression for the error function in order to express the average probability of error in terms of the two-dimensional characteristic function of the ICI.
Interactions between initiating chemical carcinogens, tumor promoters, and adenovirus in cell transformation (1981)

Cell culture systems that respond to the combined action of initiating chemical carcinogens, tumor promoters, and transforming viruses represent useful model systems for studying the complex multifactor nature of the carcinogenic process. We have utilized both secondary rat embryo (2 degrees RE) and a clonal population of established Fischer rat embryo (CREF) cells to study the effect of multiple agents on the process of adenovirus transformation. In the present review we summarize our investigations on the effects of polycyclic aromatic hydrocarbons, tumor promoters, a bee venom polypeptide-melittin (MEL), and the polypeptide hormone epidermal growth factor (EGF) on transformation of rat embryo cells by a temperature-sensitive mutant of human adenovirus type 5 (H5ts125). We also describe the effect of tumor promoters on the progression of the transformed phenotype, ie the temporal acquisition of anchorage-independent growth in adenovirus-transformed clones and the ability of MEL and EGF to elicit effects similar to those of tumor promoters in adenovirus-transformed cells.
Crossover Study of Thalidomide vs Placebo in Severe Recurrent Aphthous Stomatitis (1990)

A multicentric crossover randomized trial of 100 mg of thalidomide vs placebo each for 2 months was conducted in patients with severe aphthous stomatitis of more than 6 months' duration. Seventy-three patients were included. Complete remission was obtained in 32 patients who received thalidomide and in 6 patients who received placebo. The confidence interval of the difference between the two treatments ranged from 25% to 53%. Most of the patients who did not achieve a complete remission had a dramatic improvement with regard to the number of aphthae when they were receiving thalidomide. Thirteen of 17 patients who had a complete remission while they were receiving thalidomide had a recurrence with placebo, 19 +/- 9 (mean +/- SD) days after stopping this drug. Side effects were significantly more frequent with thalidomide, especially drowsiness and constipation. We concluded that thalidomide in a dosage of 100 mg/d is an effective treatment of severe aphthous stomatitis but is not without some risk.
Verifying atomicity via data independence (2014)

We present a technique for automatically verifying atomicity of composed concurrent operations. The main observation behind our approach is that many composed concurrent operations which occur in practice are data-independent. That is, the control-flow of the composed operation does not depend on specific input values. While verifying data-independence is undecidable in the general case, we provide succint sufficient conditions that can be used to establish a composed operation as data-independent. We show that for the common case of concurrent maps, data-independence reduces the hard problem of verifying linearizability to a verification problem that can be solved efficiently with a bounded number of keys and values. We implemented our approach in a tool called VINE and evaluated it on all composed operations from 57 real-world applications (112 composed operations). We show that many composed operations (49 out of 112) are data-independent, and automatically verify 30 of them as linearizable and the rest 19 as having violations of linearizability that could be repaired and then subsequently automatically verified. Moreover, we show that the remaining 63 operations are not linearizable, thus indicating that data independence does not limit the expressiveness of writing realistic linearizable composed operations.
High performance data mining using data cubes on parallel computers (2002)

Online analytical processing techniques are used for data analysis and decision support systems. The multidimensionality of the underlying data is well represented by multidimensional databases. For data mining in knowledge discovery, OLAP calculations can be effectively used. For these, high performance parallel systems are required to provide interactive analysis. Precomputed aggregate calculations in a data cube can provide efficient query processing for OLAP applications. We present parallel data cube construction on distributed-memory parallel computers from a relational database. The data cube is used for data mining of associations using attribute focusing. Results are presented for these on the IBM-SP2, which show that our algorithms and techniques are scalable to a large number of processors, providing a high performance platform for such applications.
Performance of resource management algorithms for "Processable Bulk Data Transfer" Tasks in Grid Environments (2008)

Processable Bulk Data Transfer (PBDT) tasks are resource intensive concurrent tasks which involve transfer of a very large amount of data that has to be processed in some way before it can be used at a remote set of destination nodes called the sink nodes. A distributed computing environment, such as the Grid is a popular way to perform these tasks. Focusing on the execution of PBDT tasks in a Grid computing environment, this paper presents an efficient resource allocation mechanism. Due to the resource thirsty nature of these tasks, an efficient resource allocation is essential to perform these tasks while achieving satisfactory performance. The time-complexity of the resource allocation algorithm rises sharply as the available number of resources in the given Grid computing environment is increased making efficient resource allocation a challenge. To meet this challenge, this paper investigates the use of approximate algorithms for the resource allocation. The benefits obtained by using the reduced complexity of the algorithm are weighed against the increased costs incurred during the task execution (due to the inaccuracies in resource allocation introduced by the approximations). This paper describes a number of approximations and discusses under which circumstances such approximations are to be used. The techniques presented in this research can be extended to non-PBDT tasks and other distributed computing environments.
Capsid Modifications for Targeting and Improving the Efficacy of AAV Vectors (2019)

In the past decade, recombinant vectors based on a non-pathogenic parvovirus, the adeno-associated virus (AAV), have taken center stage as a gene delivery vehicle for the potential gene therapy for a number of human diseases. To date, the safety of AAV vectors in 176 phase I, II, and III clinical trials and their efficacy in at least eight human diseases are now firmly documented. Despite these remarkable achievements, it has also become abundantly clear that the full potential of first generation AAV vectors composed of naturally occurring capsids is not likely to be realized, since the wild-type AAV did not evolve for the purpose of therapeutic gene delivery. In this article, we provide a brief historical account of the progress that has been made in the development of capsid-modified<b>,</b> next-generation AAV vectors to ensure both the safety and efficacy of these vectors in targeting a wide variety of human diseases.