gebhart/patrepeval huggingface dataset:
Human Mutations That Confer Paclitaxel Resistance (2010)

The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether beta1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in beta1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in beta1-tubulin may require higher drug concentrations for effective therapy.
Fast photoconductor coupled liquid-crystal light valve (1979)

Short low-energy pulses of laser light have been used to switch spots on a liquid crystal (LC) through a coupled photoconductive film of glow-discharge-produced amorphous Si (GD/a-Si). The a-Si responds rapidly to a light pulse, yet retains sufficient photoconductivity in the slow portion of the decay to match the slower response time of the LC. Spots have been written with laser pulses 10 μs long, about 10−3 the response time of the LC, and with a pulse energy of 1–10 μJ/cm2, less than 10−4 the energy required for thermal writing.
[Bioluminescence and bioluminescent analysis: development of certain aspects of the problem over the last decade]. (1993)

Recent data from gene engineering, kinetic and fluorescent studies concerning the structure and functions of firefly luciferase are reviewed. Some new trends in the development of bioluminescent methods of control over bacterial contaminations, dynamics of intracellular processes and methods of bioluminescent detection in immuno- and DNA-assays are described. Possible applications of luciferase genes as markers are considered.
Fracture Toughness Enhanced by Grain Boundary Shielding in Submicron-Grained Low Carbon Steel (2007)

The enhancement of toughness at low temperatures in fine grained low carbon steel was studied, basing on a shielding theory due to dislocations and grain boundaries. Fully annealed low carbon steel was subjected to an accumulative roll bonding (ARB) process for grain refining. The grain size perpendicular to the normal direction was found to be approximately 200 nm after the ARB process. The fracture toughness of low carbon steel ARB applied was measured at 77 K by four-point bending, comparing with the fracture toughness of those without the ARB process. It was found that the value of fracture toughness at 77 K was increased by grain refining due to the ARB, indicating that the ARB process enhances toughness at low temperatures as reported in interstitial free steel and phosphorus doped interstitial free steel. It also deduces that the brittle-ductile transition (BDT) temperature shifted to a lower temperature. The enhancement of toughness and the decrease of the BDT temperature due to grain refining cannot be explained completely by the dislocation pile-up model of dislocations at grain boundaries. Quasi-two-dimensional simulations of dislocation dynamics, taking into account of crack tip shielding due to dislocations, were performed to investigate the effect of a dislocation source spacing along a crack front on the BDT. The simulation indicated that the BDT temperature is decreased by decreasing the dislocation source spacing. In addition to the simulation, the authors suggest a new concept of accommodating stress intensity at the crack tip due to grain boundaries to explain the enhancement of toughness and the decrease of the BDT temperature in fine grained materials.
Synthesis and Evaluation of Water-Soluble Polymeric Bone-Targeted Drug Delivery Systems (2003)

Four polymeric bone-targeting conjugates were synthesized based on poly(ethylene glycol) (PEG, two conjugates) and poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA, two conjugates). The well-known bone-targeting compounds, alendronate and aspartic acid peptide, were used as bone-targeting moieties. Fluorescein isothiocyanate (FITC) was attached to the conjugates as a model drug for detection purposes. The bone-targeting potential of these conjugates was tested in vitro with hydroxyapatite (HA) and in mice. The data obtained indicated that these novel delivery systems could specifically accumulate in the bone tissue.
Prognostic and Predictive Impact of Intra- and Peritumoral Immune Infiltrates (2011)

Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients.
As Fast and Selective as Enzymatic Ligations: Unpaired Nucleobases Increase the Selectivity of DNA‐Controlled Native Chemical PNA Ligation (2005)

DNA-controlled reactions offer interesting opportunities in biological, chemical, and nanosciences. In practical applications, such as in DNA sequence analysis, the sequence fidelity of the chemical-ligation reaction is of central importance. We present a ligation reaction that is as fast as and much more selective than enzymatic T4 ligase-mediated oligonucleotide ligations. The selectivity was higher than 3000-fold in discriminating matched from singly mismatched DNA templates. It is demonstrated that this enormous selectivity is the hallmark of the particular ligation architecture, which is distinct from previous ligation architectures designed as "nick ligations". Interestingly, the fidelity of the native chemical ligation of peptide nucleic acids was increased by more than one order of magnitude when performing the ligation in such a way that an abasic-site mimic was formed opposite an unpaired template base. It is shown that the high sequence fidelity of the abasic ligation could facilitate the MALDI-TOF mass-spectrometric analysis of early cancer onset by allowing the detection of as little as 0.2 % of single-base mutant DNA in the presence of 99.8 % wild-type DNA.
Image thresholding by indicator kriging (1999)

We consider the problem of segmenting a digitized image consisting of two univariate populations. Assume a priori knowledge allows incomplete assignment of voxels in the image, in the sense that a fraction of the voxels can be identified as belonging to population II/sub 0/, a second fraction to II/sub 1/, and the remaining fraction have no a priori identification. Based upon estimates of the short length scale spatial covariance of the image, we develop a method utilizing indicator kriging to complete the image segmentation.
Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology (2013)

The use of primary mammalian neurons derived from embryonic central nervous system tissue is limited by the fact that once terminally differentiated into mature neurons, the cells can no longer be propagated. Transformed neuronal-like cell lines can be used in vitro to overcome this limitation. However, several caveats exist when utilizing cells derived from malignant tumors. In this context, the popular SH-SY5Y neuroblastoma cell line and its use in in vitro systems is described. Originally derived from a metastatic bone tumor biopsy, SH-SY5Y (ATCC(®) CRL-2266™) cells are a subline of the parental line SK-N-SH (ATCC(®) HTB-11™). SK-N-SH were subcloned three times; first to SH-SY, then to SH-SY5, and finally to SH-SY5Y. SH-SY5Y were deposited to the ATCC(®) in 1970 by June L. Biedler.Three important characteristics of SH-SY5Y cells should be considered when using these cells in in vitro studies. First, cultures include both adherent and floating cells, both types of which are viable. Few studies address the biological significance of the adherent versus floating phenotypes, but most reported studies utilize adherent populations and discard the floating cells during media changes. Second, early studies by Biedler's group indicated that the parental differentiated SK-N-SH cells contained two morphologically distinct phenotypes: neuroblast-like cells and epithelial-like cells (Ross et al., J Nat Cancer Inst 71:741-747, 1983). These two phenotypes may correspond to the "N" and "S" types described in later studies in SH-SY5Y by Encinas et al. (J Neurochem 75:991-1003, 2000). Cells with neuroblast-like morphology are positive for tyrosine hydroxylase (TH) and dopamine-β-hydroxylase characteristic of catecholaminergic neurons, whereas the epithelial-like counterpart cells lacked these enzymatic activities (Ross et al., J Nat Cancer Inst 71:741-747, 1983). Third, SH-SY5Y cells can be differentiated to a more mature neuron-like phenotype that is characterized by neuronal markers. There are several methods to differentiate SH-SY5Y cells and are mentioned below. Retinoic acid is the most commonly used means for differentiation and will be addressed in detail.
Beta protein C is not glycosylated at asparagine 329. The rate of translation may influence the frequency of usage at asparagine-X-cysteine sites. (1990)

About 30% of human plasma protein C is smaller than the predominant form as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. It has been suggested that this species, referred to as beta protein C, is a degraded molecule. However, beta protein C is secreted in culture by the HepG2 cell line and is present in plasma collected directly into numerous proteinase inhibitors; the percentage of beta protein C does not change with time during culture or after blood collection. Neither thrombin, activated protein C, nor activated factor X converts the alpha form to beta in the presence or absence of calcium and phospholipids. The NH2-terminal sequences of the heavy chains of both forms are identical, and both release the same dodecapeptide and develop a functional active site when cleaved by thrombin. Both also react with antibodies to a synthetic COOH-terminal peptide. Timed digests with N-glycosidase are consistent with the interpretation that beta protein C has three N-linked oligosaccharide chains whereas alpha protein C has four. It is asparagine 329 that is not glycosylated in beta protein C since antibodies to a synthetic peptide based on the sequence around this amino acid react only with beta protein C. This site is unique in having cysteine instead of serine or threonine 2 residues distal. It is likely that the sulfhydryl group can substitute for the usual hydroxyl group as a hydrogen bond acceptor for the glycosylation reaction only until it forms a disulfide bond. The percentage of protein C that is glycosylated at this site may therefore depend at least in part on the rate of disulfide bond formation which may in turn be related to the rate of protein synthesis.
Analysis of a C-methyltransferase gene (aviG1) involved in avilamycin biosynthesis in Streptomyces viridochromogenes Tü57 and complementation of a Saccharopolyspora erythraea eryBIII mutant by aviG1 The GenBank accession number for the sequence reported in this paper is AF333038. (2002)

Streptomyces viridochromogenes Tü57 is the principal producer of avilamycin A. aviG1, a putative methyltransferase gene, was detected in the avilamycin biosynthetic gene cluster. To determine the function of aviG1, a targeted gene inactivation experiment was performed. The resulting chromosomal mutant, carrying an in-frame deletion in aviG1, was deficient in avilamycin production. aviG1 was used to complement an eryBIII mutant of the erythromycin A producer Saccharopolyspora erythraea [Gaisser, S., Bohm, G. A., Doumith, M., Raynal, M. C., Dhillon, N., Cortes, J. & Leadlay, P. F. (1998). Mol Gen Genet 258, 78-88]. The presence of erythromycin A in the culture supernatant of the complemented mutant indicated that L-mycarose biosynthesis could be restored and that AviG1 could take over the function of the C-methyltransferase EryBIII.
ONE POT SYNTHESIS OF NUCLEOSIDE 5′-THIOPHOSPHORAMIDATES (2002)

ABSTRACT Nucleoside 5′-thiophosphoramidates were synthesized through a highly efficient approach; i.e., thiophosphoryl chloride was sequentially treated with an amino acid methyl ester and a protected or unprotected nucleoside. The product was then hydrolyzed in 2 M NH4OH.
A safety-oriented platform for Web applications (2006)

This paper describes the architecture and implementation of the Tahoma Web browsing system. Key to Tahoma is the browser operating system (BOS), a new trusted software layer on which Web browsers execute. The benefits of this architecture are threefold. First, the BOS runs the client-side component of each Web application (e.g., on-line banking, Web mail) in its own virtual machine. This provides strong isolation between Web services and the user's local resources. Second, Tahoma lets Web publishers limit the scope of their Web applications by specifying which URLs and other resources their browsers are allowed to access. This limits the harm that can be caused by a compromised browser. Third, Tahoma treats Web applications as first-class objects that users explicitly install and manage, giving them explicit knowledge about and control over downloaded content and code. We have implemented a prototype of Tahoma using Linux and the Xen virtual machine monitor. Our security evaluation shows that Tahoma can prevent or contain 87% of the vulnerabilities that have been identified in the widely used Mozilla browser. In addition, our measurements of latency, throughput, and responsiveness demonstrate that users need not sacrifice performance for the benefits of stronger isolation and safety
Phytoestrogens activate estrogen receptor β1 and estrogenic responses in human breast and bone cancer cell lines (2007)

Plant-derived phytoestrogens and estrogens in hormone replacement therapies have overlapping yet sometimes divergent effects on the incidence of breast cancer and osteoporosis. Using human MCF-7 breast carcinoma and G-292 osteosarcoma cell lines, it was investigated whether the phytoestrogens genistein and daidzein affect reporter gene transcription via the estrogen receptors (ERs) ERalpha and ERbeta1 as well as whether they affect the expression of estrogen-responsive genes in MCF-7 cells and the secretion of the cytokine IL-6 from G-292 cells. The results showed that genistein and daidzein potently trigger transactivation with ERbeta1 from estrogen response element-reporter genes (EC50s of 1.7-16 nM) although they were 400- to 600-fold less potent than 17beta-estradiol (E2) (EC50 of 0.02-0.04 nM). E2 was the only potent activator of ERalpha (EC50 of 0.1-0.4 nM). The rank order potency (E2 > genistein > daidzein) is maintained in MCF-7 cells as well as G-292 cells with both receptor subtypes, with a strong receptor selectivity of the phytoestrogens for ERbeta1 over ERalpha. Genistein and daidzein increased the expression of estrogen-responsive genes in MCF-7 cells. Daidzein, like E2, inhibited IL-1beta- and hormone-mediated IL-6 secretion from G-292 cells. The results provide a basis for understanding how dietary phytoestrogens protect bone without increasing the risks for breast cancer.
REVISED SYNTHESIS OF SOME NEW DERIVATIVES OF BIOLOGICAL INTEREST 2-HETEROCYCLIC BENZOTHIAZOLYL DERIVATIVES OF BIOLOGICAL INTEREST (1999)

Abstract Substituted benzothiazole at position 2 by a heterocyclic ring has been prepared by the action of bifunctional compounds on the active intermediate a-2-benzoth: azolyl-β-arylaminoacrylonitrile (III). Compound III was obtained by refluxing a-2-benzothiazolyl-β, β-dimethylthioacrylonitrile (II) with aromatic amines in ethanol for a long time. Refluxing equimolar amounts of I11 and hydrazine, hydroxylamine, guandine ethylenediamine and ethanolamine in presence of DMF yielded the corresponding 2-pyra- 2010, isoxazolo, pyrimidino, 1,4-diazepino and 1,4-oxazepinobenzothiazole (V-IX), respectively. The structures of all newly prepared compounds have been confirmed by analytical and spectral data.
Selectivity and Promiscuity of the First and Second PDZ Domains of PSD-95 and Synapse-associated Protein 102 (2002)

PDZ domains typically interact with the very carboxyl terminus of their binding partners. Type 1 PDZ domains usually require valine, leucine, or isoleucine at the very COOH-terminal (P(0)) position, and serine or threonine 2 residues upstream at P(-2). We quantitatively defined the contributions of carboxyl-terminal residues to binding selectivity of the prototypic interactions of the PDZ domains of postsynaptic density protein 95 (PSD-95) and its homolog synapse-associated protein 90 (SAP102) with the NR2b subunit of the N-methyl-d-aspartate-type glutamate receptor. Our studies indicate that all of the last five residues of NR2b contribute to the binding selectivity. Prominent were a requirement for glutamate or glutamine at P(-3) and for valine at P(0) for high affinity binding and a preference for threonine over serine at P(-2), in the context of the last 11 residues of the NR2b COOH terminus. This analysis predicts a COOH-terminal (E/Q)(S/T)XV consensus sequence for the strongest binding to the first two PDZ domains of PSD-95 and SAP102. A search of the human genome sequences for proteins with a COOH-terminal (E/Q)(S/T)XV motif yielded 50 proteins, many of which have not been previously identified as PSD-95 or SAP102 binding partners. Two of these proteins, brain-specific angiogenesis inhibitor 1 and protein kinase Calpha, co-immunoprecipitated with PSD-95 and SAP102 from rat brain extracts.
Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21 (2010)

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
Extending the Applicability of Carboxyfluorescein in Solid-Phase Synthesis (2003)

Optimized coupling protocols are presented for the efficient and automated generation of carboxyfluorescein-labeled peptides. Side products, generated when applying earlier protocols for the in situ activation of carboxyfluorescein, were eliminated by a simple procedure, yielding highly pure fluorescent peptides and minimizing postsynthesis workup. For the cost-efficient labeling of large compound collections, coupling protocols were developed reducing the amount of coupling reagent and fluorophore. To enable further chemical derivatization of carboxyfluorescein-labeled peptides in solid-phase synthesis, the on-resin introduction of the trityl group was devised as a protecting group strategy for carboxyfluorescein. This protecting group strategy was exploited for the synthesis of peptides labeled with two different fluorescent dyes, essential tools for bioanalytical applications based on fluorescence resonance energy transfer (FRET). Tritylation and optimized labeling conditions led to the development of a fluorescein-preloaded resin for the automated synthesis of fluorescein-labeled compound collections with uniform labeling yields.
Array-Based Sensing of Proteins Using Conjugated Polymers (2007)

A sensor array comprising six functionalized poly(p-phenyleneethynylene) polymers was constructed and used to detect and identify protein analytes. The presence of proteins alters the fluorescence properties of the polymers, generating a distinct fluorescence response pattern for a given protein. Linear discriminant analyses accurately differentiate the patterns of 17 proteins at nano- to micromolar concentrations. An identification accuracy of 97% was obtained on the basis of the tests with 68 unknown protein samples from the training set.