gebhart/patrepeval huggingface dataset:
Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction (2006)

The molecular chaperone hsp90 has emerged as an important therapeutic target in cancer and neurodegenerative diseases, including the polyglutamine expansion disorders, because of its ability to regulate the activity, turnover and trafficking of many proteins. For neurodegenerative disorders associated with protein aggregation, the rationale has been that inhibition of hsp90 by geldanamycin and related compounds activates heat shock factor 1 (HSF1) to induce the production of the chaperones hsp70 and hsp40 that promote disaggregation and protein degradation. However, we show here that geldanamycin blocks the development of aggregates of the expanded glutamine androgen receptor (AR112Q) of Kennedy disease in Hsf1(-/-) mouse embryonic fibroblasts where these chaperones are not induced. Geldanamycin is additionally known to inhibit hsp90-dependent protein trafficking and to promote proteasomal degradation of client proteins. Overexpression of the hsp90 cochaperone p23 also promotes AR112Q degradation, and inhibits both AR trafficking and AR112Q aggregation without altering levels of hsp70 or hsp40. The hsp90-dependent trafficking mechanism has been defined, and it is shown that key immunophilin (IMM) components of the trafficking machinery are present in polyglutamine aggregates in cell and mouse models of Kennedy disease. Our results indicate that inhibition of the hsp90-dependent trafficking mechanism prevents aggregation of the expanded glutamine androgen receptor, thereby opening a variety of novel therapeutic approaches to these neurodegenerative disorders.
Burst and continuous high frequency irreversible electroporation protocols evaluated in a 3D tumor model (2018)

High frequency irreversible electroporation (H-FIRE) is an emerging cancer therapy which uses bursts of alternating polarity pulses to target and destroy the membranes of cells within a predictable volume. Typically, 2 µs pulses are rapidly repeated 24-50 times to create a 48-100 µs long energy burst. Bursts are repeated 100× at 1 Hz, resulting in an integrated energized time of 0.01 s per treatment. A 3D in vitro tumor model was used to investigate H-FIRE parameters in search of optimal energy timing protocols. Monopolar IRE treatments (100 × 100 µs positive polarity pulses) resulted in a lethal electric field threshold of 423 V cm<sup>-1</sup>. Baseline H-FIRE treatments (100 × 100 µs bursts of 2 µs pulses) resulted in a lethal threshold of 818 V cm<sup>-1</sup>. Increasing the number of H-FIRE bursts from 100× to 1000× reduced the lethal threshold to 535 V cm<sup>-1</sup>. An alternative diffuse H-FIRE protocol, which delivers 4 µs pulse cycles (one positive and one negative 2 µs pulse) continuously at 100 Hz, resulted in the lowest H-FIRE lethal threshold of 476 V cm<sup>-1</sup>. Finite element simulations using 5 kV pulses predict an IRE ablation volume of 3.9 cm<sup>3</sup> (1.7 cm diameter) and a maximum H-FIRE ablation volume of 5.3 cm<sup>3</sup> (2.4 cm diameter) when a clinical electrode and grounding pad configuration is used. Ablations as large as 15.7 cm<sup>3</sup> (3.3 cm diameter) are predicted for H-FIRE treatments with 10 kV pulses. These results combine to demonstrate the importance of electrode geometry, pulse timing, and clinical delivery protocols for the creation of large clinically meaningful ablations.
Induction of strong antitumor immunity by an HSV‐2‐based oncolytic virus in a murine mammary tumor model (2007)

Oncolytic viruses have shown considerable promise for the treatment of solid tumors. In previous studies, we demonstrated that a novel oncolytic virus (FusOn-H2), constructed by replacing the serine/threonine protein kinase (PK) domain of the ICP10 gene of type 2 herpes simplex virus (HSV-2) with the gene encoding the green fluorescent protein, can selectively replicate in and thus lyse tumor cells. 4T1 tumor cells are weakly immunogenic and the mammary tumors derived from them aggressively metastasize to different parts of body, thus providing an attractive model for evaluating anticancer agents. We thus tested the antitumor effect of FusOn-H2 in this tumor model, in comparisons with several other oncolytic HSVs derived from HSV-1, including a nonfusogenic HSV-1 (Baco-1) and a doubly fusogenic virus (Synco-2D). Our results show that FusOn-H2 and Synco-2D have greater oncolytic activity in vitro than Baco-1. Moreover, FusOn-H2 induced strong T cell responses against primary and metastatic mammary tumors in vivo, and splenocytes adoptively transferred from FusOn-H2-treated mice effectively prevented metastasis in naïve mice bearing implanted mammary tumors. We conclude that the HSV-2-based FusOn-H2 oncolytic virus may be an effective agent for the treatment of both primary and metastatic breast cancer.
Image analysis methods for localization of visual codes (2016)

Az élet számos területén alkalmazunk vizuális kódokat a legkülönfélébb dolgok azonosítására (pl. bolti árucikkek, postai küldemények, áramköri alkatrészek). A kódok nagyon változatosak lehetnek típus (pl. 1D barcode, 2D datamatrix, OCR karaktersorozat), méret (pl. néhány száz mikron, néhány centiméter, vagy akár 1 méter), és előállítási technika (pl. nyomtatás, mikrogravírozás) szerint. A kódok letapogatására leggyakrabban 2D digitális kamerás vagy vonalszkenneres technikákat alkalmaznak. A kódot hordozó felület torzulásai mellett az egyenetlen megvilágítás és a mérés pontatlanságai is komoly problémákat jelentenek a detektáló algoritmusoknak. Mindezek mellett a feldolgozáshoz rendelkezésre álló erőforrások korlátai valamint a feldolgozás sebességére és pontosságára szabott szigorú feltételek is komoly kihívásokat jelentenek a gyakorlatban. A disszertáció témája előfeldolgozási és képszűrési módszerek vizsgálata, különféle kódot tartalmazó régiók detektálásához kép-alapú jellemzők vizsgálata és újak kidolgozása, valamint hatékony és megbízható algoritmusok kifejlesztése, melyek könnyen adaptálhatók különféle valódi alkalmazási területekre.
HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality (2009)

Our results indicate that hepatitis C is a major health problem and highlight the importance of timely antiviral treatment. However, data on the burden of disease of hepatitis C in Europe are scarce, outdated or inconclusive, which indicates that hepatitis C is still a neglected disease in many countries. What is needed are public awareness, co-ordinated action plans, and better data. European physicians should be aware that many infections are still undetected, provide timely testing and antiviral treatment, and avoid iatrogenic transmission.
Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. (1994)

The prevalence of PAI-1 expression within pulmonary thromboemboli suggests that this inhibitory may play a role in the stabilization of vascular thrombi.
Topology of the phenylalanine-specific permease of Escherichia coli (1996)

The PheP protein is a high-affinity phenylalanine-specific permease of the bacterium Escherichia coli. A topological model based on sequence analysis of the putative protein in which PheP has 12 transmembrane segments with both N and C termini located in the cytoplasm had been proposed (J. Pi, P. J. Wookey, and A. J. Pittard, J. Bacteriol. 173:3622-3629, 1991). This topological model of PheP has been further examined by generating protein fusions with alkaline phosphatase. Twenty-five sandwich fusion proteins have been constructed by inserting the 'phoA gene at specific sites within the pheP gene. In general, the PhoA activities of the fusions support a PheP topology model consisting of 12 transmembrane segments with the N and C termini in the cytoplasm. However, alterations to the model, affecting spans III and VI, were indicated by this analysis and were supported by additional site-directed mutagenesis of some of the residues involved.
The Demise of Follicular Carcinoma of the Thyroid Gland (1994)

Over the past several decades, iodide supplementation to food supplies in many parts of the world has been followed by a corresponding decrease in the incidence of follicular thyroid carcinoma. However, pathologists continue to over-diagnose this tumor. Benign lesions (e.g., partly encapsulated hyperplastic nodules, pseudoinvasion after fine needle aspiration), and malignancies (especially the follicular variant of papillary carcinoma) have been misinterpreted as follicular carcinoma. Since the clinical features and biological behavior of true follicular cancer differ from the entities with which it may be confused, it is essential that appropriate histological criteria be applied to the diagnostic interpretation of thyroid nodules that exhibit follicular architecture. Only in this way will it be possible to define prognosis and to evaluate treatment options.
Pharmacokinetics of teceleukin (recombinant human interleukin-2) after intravenous or subcutaneous administration to patients with cancer. (1989)

Single doses of teceleukin ranging from 0.1 to 30 x 10(6) units were administered to cancer patients as intravenous infusions or subcutaneous injections. Serum samples were analyzed using a bioassay. In general, teceleukin was rapidly eliminated after intravenous administration, with half-lives ranging from 0.24 to 3.3 h. Teceleukin disappeared from serum more slowly following subcutaneous administration, with half-lives of 2.7 to 12.2 h. This finding may be a result of slow absorption from the subcutaneous injection site. Serum concentrations of teceleukin increased in an apparently dose-proportional manner following intravenous administration. When administered subcutaneously, serum concentrations increased with increasing dose but in a manner that was less than dose-proportional, possibly due to dose-dependent bioavailability for subcutaneously administered teceleukin.
Detection and characterization of MuSK antibodies in seronegative myasthenia gravis (2004)

Antibodies to rat muscle specific kinase, MuSK, have recently been identified in some generalized "seronegative" myasthenia gravis (SNMG) patients, who are often females with marked bulbar symptoms. Using immunoprecipitation of (125)I-labelled-human MuSK, 27 of 66 (41%) seronegative patients were positive, but 18 ocular SNMG patients, 105 AChR antibody positive MG patients, and 108 controls were negative. The antibodies are of high affinity (Kds around 100 pM) with titers between 1 and 200 nM. They bind to the extracellular Ig-like domains of soluble or native MuSK. Surprisingly they are predominantly in the IgG4 subclass. MuSK-antibody associated MG may be different in etiological and pathological mechanisms.
Activity of novel RET inhibitors against RET genotypes associated with medullary thyroid cancer. (2010)

5559 Background: Point mutations in RET tyrosine kinase, most commonly C634R and M918T, result in the development of medullary thyroid cancer (MTC). C634R and M918T occur in the cysteine-rich and kinase domain, respectively, and therefore activate RET by differing mechanisms. V804L, a mutation at the putative RET gatekeeper residue, has demonstrated resistance to several tyrosine kinase inhibitors (TKIs) in vitro. Notably, with other tyrosine kinases, mutations in the kinase domains or gatekeeper residues alter drug sensitivity. We evaluated the effect of these RET mutations on the response to TKIs in a cell based system. Methods: CHO cells expressing WT and mutant RET proteins were treated with a panel of TKIs consisting of compounds in preclinical development (DP-2490 and DP-3636) and drugs being studied for treatment of MTC in clinical trials (axitinib, motesanib, sorafenib, sunitinib, vandetanib). Drug sensitivity was determined by inhibition of RET kinase phosphorylation and IC50s were calculated using photodensitometry. Results: The IC50s of each TKI against the different RET mutants are presented in the Table. WT RET was most sensitive to all of the TKIs. DP-2490 and DP-3636 had IC50s < 1 nM against WT RET, and demonstrated superior potency against all of the RET mutants tested. All drugs tested were at least 5-fold more potent against C634R than M918T. V804L demonstrated complete resistance to axitinib, motesanib, and vandetanib at 5,000nM, but demonstrated increased sensitivity to the other compounds when compared to M918T. Conclusions: RET kinase is a therapeutic target for the treatment of MTC. Here, we demonstrate that RET kinase inhibition differs by RET genotype and kinase inhibitor. These findings are similar to those in other malignancies, and suggest that MTC tumor genotype may be predictive of response to individual TKIs that target RET. DP-2490 and DP-3636 represent the most potent RET inhibitors described to date and should be studied further for the treatment of MTC. Inhibitor IC50 (nM) RET wild-type RET C634R RET V804L RET M918T Axitinib 50 130 >5,000 2,350 Motesanib 150 250 >5,000 1,870 Sorafenib 30 60 390 430 Sunitinib 13 70 40 360 Vandetanib 60 110 >5,000 560 DP-2490 0.4 10 30 86 DP-3636 0.1 0.7 1.4 10 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Deciphera Deciphera
Kinetic and mechanistic analyses of new classes of inhibitors of two-component signal transduction systems using a coupled assay containing HpkA–DrrA from Thermotoga maritima (2004)

Two-component signal transduction systems (TCSs) play fundamental roles in bacterial survival and pathogenesis and have been proposed as targets for the development of novel classes of antibiotics. A new coupled assay was developed and applied to analyse the kinetic mechanisms of three new kinds of inhibitors of TCS function. The assay exploits the biochemical properties of the cognate HpkA-DrrA histidine kinase-response regulator pair from Thermotoga maritima and allows multiple turnovers of HpkA, linear formation of phosphorylated DrrA, and Michaelis-Menten analysis of inhibitors. The assay was validated in several ways, including confirmation of competitive inhibition by adenosine 5'-beta,gamma-imidotriphosphate (AMP-PNP). The coupled assay, autophosphorylation and chemical cross-linking were used to determine the mechanisms by which several compounds inhibit TCS function. A cyanoacetoacetamide showed non-competitive inhibition with respect to ATP concentration in the coupled assay. The cyanoacetoacetamide also inhibited autophosphorylation of histidine kinases from other bacteria, indicating that the coupled assay could detect general inhibitors of histidine kinase function. Inhibition of HpkA autophosphorylation by this compound was probably caused by aggregation of HpkA, consistent with a previous model for other hydrophobic compounds. In contrast, ethodin was a potent inhibitor of the combined assay, did not inhibit HpkA autophosphorylation, but still led to aggregation of HpkA. These data suggest that ethodin bound to the HpkA kinase and inhibited transfer of the phosphoryl group to DrrA. A peptide corresponding to the phosphorylation site of DrrA appeared to inhibit TCS function by a mechanism similar to that of ethodin, except that autophosphorylation was inhibited at high peptide concentrations. The latter mechanism of inhibition of TCS function is unusual and its analysis demonstrates the utility of these approaches to the kinetic analyses of additional new classes of inhibitors of TCS function.
Protein Quantification in Complex Mixtures by Solid Phase Single-Molecule Counting (2009)

Here we present a procedure for quantifying single protein molecules affixed to a surface by counting bound antibodies. We systematically investigate many of the parameters that have prevented the robust single-molecule detection of surface-immobilized proteins. We find that a chemically adsorbed bovine serum albumin surface facilitates the efficient detection of single target molecules with fluorescent antibodies, and we show that these antibodies bind for lengths of time sufficient for imaging billions of individual protein molecules. This surface displays a low level of nonspecific protein adsorption so that bound antibodies can be directly counted without employing two-color coincidence detection. We accurately quantify protein abundance by counting bound antibody molecules and perform this robustly in real-world serum samples. The number of antibody molecules we quantify relates linearly to the number of immobilized protein molecules (R(2) = 0.98), and our precision (1-5% CV) facilitates the reliable detection of small changes in abundance (7%). Thus, our procedure allows for single, surface-immobilized protein molecules to be detected with high sensitivity and accurately quantified by counting bound antibody molecules. Promisingly, we can probe flow cells multiple times with antibodies, suggesting that in the future it should be possible to perform multiplexed single-molecule immunoassays.
Noisy speech recognition using cepstral-time features and spectral-time filters (2002)

This paper explores the advantages of using cepstral-time feature matrices, and spectral-time filters, for noisy speech recognition within a hidden Markov model framework. The use of cepstral-time features with spectral subtraction and state-based time-varying Wiener filters is investigated. Experimental results indicate that cepstral-time features, and spectral-time noise processing, provide an effective framework for robust speech recognition in noisy environments.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Spontaneous ultraweak bioluminescence in plants: origin, mechanisms and properties. (1998)

An analysis of theoretical knowledge and experimental results of ultraweak luminescence (UWL) is provided. The role of excited state of molecules and free radicals, formed in various biochemical reactions, in UWL is discussed. UWL of model reactions and in vivo systems are compared. The hypothesis of coherent electromagnetic field as a source of UWL is also discussed. Spectral, kinetic and temporal properties of UWL are summarised, as well as their connection with its origin and role in the organism. Attention is paid to recent progress in experimental methods of low-light detection. The possible use of UWL in environmental studies, selection and other applications is discussed.
Aminooxy Functionalized Oligonucleotides:  Preparation, On-Support Derivatization, and Postsynthetic Attachment to Polymer Support (1999)

Three novel phosphoramidites, each bearing a phthaloyl-protected aminooxy tail, were prepared and applied in automated oligonucleotide synthesis. After chain assembly, the phthaloyl protection was removed with hydrazinium acetate. Normal succinyl linker turned to be stable under these conditions, and hence the support-bound oligonucleotide could be converted to a pyrene oxime conjugates by reacting with pyrene carbaldehyde or cis-retinal. Standard ammonolytic deprotection then released the deprotected conjugate in solution. Alternatively, the crude aminooxy-tethered oligonucleotide was immobilized to microscopic polymer particles by reacting the aminooxy function with the particle-bound aldehyde or epoxide groups. These immobilized oligonuceotides were shown to serve properly as probes in a mixed phase hybridization assay.
Contribution of molecular oncology in the detection of colorectal carcinomas. (1996)

The development of effective screening tests for colorectal tumors is essential given the high frequency of these cancers in the general population, and more especially in various groups at risk. Sporadic and hereditary colorectal cancers result from the accumulation of mutations in oncogenes, such as ras, myc, neu/HER2, and in tumor suppressor genes such as apc, dcc, p53. The detection of ras or p53 mutations in DNA extracted from stool has been shown to be feasible and might be useful for the development of new screening tests. Many mutations in these genes can also be used as new prognostic factors. Identification of mutation in the apc gene responsible for familial polyposis, or its indirect detection through the study of polymorphism in such families, is completely changing the previously recommended medical attitude for the screening of this disease, and therefore may decrease or even avoid major medical follow-up. These changes are also true for the nonpolyposis hereditary colorectal tumors, also called Lynch syndrome, since the responsible hMSH2, hMLH1, hPMS1 and hPMS2 genes have recently been cloned. Mutations in these genes do not seem to be limited to families with Lynch syndrome, and could account for a predisposition of some patients to develop colorectal or other tumors.
Hydrogen Storage in New Metal–Organic Frameworks (2012)

Five new metal–organic frameworks (MOFs, termed MOF-324, 325, 326 and IRMOF-61 and 62) of either short linkers (pyrazolecarboxylate and pyrazaboledicarboxylate) or long and thin alkyne functionalities (ethynyldibenzoate and butadiynedibenzoate) were prepared to examine their impact on hydrogen storage in MOFs. These compounds were characterized by single-crystal X-ray diffraction, and their low-pressure and high-pressure hydrogen uptake properties were investigated. In particular, volumetric excess H2 uptake by MOF-324 and IRMOF-62 outperforms MOF-177 up to 30 bar. Inelastic neutron-scattering studies for MOF-324 also revealed strong interactions between the organic links and hydrogen, in contrast to MOF-5 where the interactions between the Zn4O unit and hydrogen are the strongest. These data also show that smaller pores and polarized linkers in MOFs are indeed advantageous for hydrogen storage.
Identification of siRNA delivery enhancers by a chemical library screen (2015)

Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve delivery is to identify small molecules enhancing these steps. It is unclear to what extent such enhancers can be universally applied to different delivery systems and cell types. Here, we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing 2-5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types.
Image partial blur detection and classification (2008)

In this paper, we propose a partially-blurred-image classification and analysis framework for automatically detecting images containing blurred regions and recognizing the blur types for those regions without needing to perform blur kernel estimation and image deblurring. We develop several blur features modeled by image color, gradient, and spectrum information, and use feature parameter training to robustly classify blurred images. Our blur detection is based on image patches, making region-wise training and classification in one image efficient. Extensive experiments show that our method works satisfactorily on challenging image data, which establishes a technical foundation for solving several computer vision problems, such as motion analysis and image restoration, using the blur information.