gebhart/patrepeval huggingface dataset:
Modelling prior distributions of atoms for macromolecular refinement and completion (2000)

Until modelling is complete, macromolecular structures are refined in the absence of a model for some of the atoms in the crystal. Techniques for defining positional probability distributions of atoms, and using them to model the missing part of a macromolecular crystal structure and the bulk solvent, are described. The starting information may consist of either a tentative structural model for the missing atoms or an electron-density map. During structure completion and refinement, the use of probability distributions enables the retention of low-resolution phase information while avoiding premature commitment to uncertain higher resolution features. Homographic exponential modelling is proposed as a flexible, compact and robust parametrization that proves to be superior to a traditional Fourier expansion in approximating a model protein envelope. The homographic exponential model also has potential applications to ab initio phasing of Fourier amplitudes associated with macromolecular envelopes.
Novel mechanism(s) of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. (1992)

Mechanisms of resistance to 5-fluorouracil (FUra) were compared between a cell line resistant to a short-term exposure (4 h) to this agent (HCT-8/FU4hR) and a cell line resistant to a prolonged exposure (7 days) to the fluoropyrimidine (HCT-8/FU7dR). The two cell lines were obtained by repeatedly exposing 2 x 10(5) cells to a constant concentration of FUra (1000 microM for 4 h or 15 microM for 7 days), able to produce 3-4 logs of cell kill. HCT-8/FU4hR cells were still sensitive to FUra given as a 7-day exposure, suggesting different mechanisms of resistance. In addition, HCT-8/FU7dR cells were cross-resistant to fluorodeoxyuridine and, to a lesser degree, methotrexate; while HCT-8/FU4dR cells were not. Both HCT-8/FU4hR and HCT-8/FU7dR cells were similar to parental HCT-8 cells with regard to uptake of FUra as well as the pattern of FUra-metabolizing and FUra target enzymes. Although neither in situ thymidylate synthase (TS) activity nor the degree of its inhibition by FUra showed any evidence of alteration in HCT-8/FU7dR cells, a rapid recovery of TS activity after drug removal was evident in this cell line. The addition of as much as 100 microM leucovorin did not completely inhibit the recovery of thymidylate synthesis after FUra exposure. No differences were detected in the kinetic properties (Km for 2'-deoxyuridylate and 5,10-methylenetetrahydrofolate, concentration producing 50% inhibition for fluorodeoxyuridylate) or TS from HCT-8/FU7dR cells as compared to parental HCT-8 TS. Baseline levels of 5,10 methylenetetrahydrofolate were decreased in HCT-8/FU7dR cells, and analysis of the chain length distribution of the polyglutamylated form of the folate cofactor showed that in this cell line the defect in 5,10-methylenetetrahydrofolate levels is accompanied by, and possibly due to, a defect in the polyglutamylation of this cofactor. In contrast, HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS inhibition by FUra and duration of inhibition after FUra removal. Labeling studies with [3H-6]FUra (4 h exposure, 100 microM) showed that the incorporation of the fluoropyrimidine into RNA is significantly decreased in HCT-8/FU4hR cells as compared to parental HCT-8 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus (2007)

HMGB1 is a pro-inflammatory cytokine that together with TNF-alpha and IL-1beta is involved in the pathogenesis of spontaneously occurring skin lesions in lupus erythematosus. The purpose of the present study was to explore the sequence of events in HMGB1, TNF-alpha and IL-1beta expression under development and resolution of experimentally induced CLE lesions. The study involved investigation of 38 serial skin biopsies acquired from photoprovoked skin lesions of nine CLE patients, using immunohistochemical staining of tissue sections. In biopsies from the clinically most active phase of skin involvement extracellular, secreted HMGB1 and increased cytoplasmic HMGB1 were found, as compared with the late and fading lesions or non-lesional skin. Besides HMGB1, increased expression of TNF-alpha and IL-1beta was observed in dermal infiltrates of the induced CLE lesions. These cytokines were however not upregulated in all lesions, and increased expression of IL-1beta was seen predominantly in late biopsies.In conclusion, extracellular and cytoplasmic HMGB1 coincides with the clinically most active phase of photoinduced lesions of cutaneous lupus, and suggests that HMGB1 is an important factor in the inflammatory autoimmune process of CLE. HMGB1 can induce expression of TNF-alpha and IL-1beta, and formation of a pro-inflammatory loop between HMGB1, TNF-alpha, and IL-1beta may be responsible for the prolonged and sustained inflammation in CLE.
Molecular Epidemiologic Evaluation of Transmissibility and Virulence of Mycobacterium tuberculosis (1999)

Discovery of genotypic markers associated with increased transmissibility in Mycobacterium tuberculosis would represent an important step in advancing mycobacterial virulence studies. M. tuberculosis strains may be classified into one of three genotypes on the basis of the presence of specific nucleotide substitutions in codon 463 of the katG gene (katG-463) and codon 95 of the gyrA gene (gyrA-95). It has previously been reported that two of these three genotypes are associated with increased IS6110-based clustering, a potential proxy of virulence. We designed a case-control analysis of U.S.-born patients with tuberculosis in San Francisco, Calif., between 1991 and 1997 to investigate associations between katG-463 and gyrA-95 genotypes and epidemiologically determined measures of strain-specific infectivity and pathogenicity and IS6110-based clustering status. We used a new class of molecular probes called molecular beacons to genotype the isolates rapidly. Infectivity was defined as the propensity of isolates to cause tuberculin skin test conversions among named contacts, and pathogenicity was defined as their propensity to cause active disease among named contacts. The molecular beacon assay was a simple and reproducible method for the detection of known single nucleotide polymorphisms in large numbers of clinical M. tuberculosis isolates. The results showed that no genotype of the katG-463- and gyrA-95-based classification system was associated with increased infectivity and pathogenicity or with increased IS6110-based clustering in San Francisco during the study period. We speculate that molecular epidemiologic studies investigating clinically relevant outcomes may contribute to the knowledge of the significance of laboratory-derived virulence factors in the propagation of tuberculosis in human communities.
Gene Structures and Regulation of the Alkane Hydroxylase Complex in Acinetobacter sp. Strain M-1 (2001)

In the long-chain n-alkane degrader Acinetobacter sp. strain M-1, two alkane hydroxylase complexes are switched by controlling the expression of two n-alkane hydroxylase-encoding genes in response to the chain length of n-alkanes, while rubredoxin and rubredoxin ruductase are encoded by a single gene and expressed constitutively.
Id2 Is Dispensable for Myc-Induced Epidermal Neoplasia (2004)

We have previously described a transgenic mouse model of epidermal neoplasia wherein expression of a switchable form of c-Myc, MycER(TAM), is targeted to the postmitotic suprabasal keratinocytes of murine epidermis via the involucrin promoter. Sustained activation of c-MycER(TAM) results in a progressive neoplastic phenotype characterized by aberrant ectopic proliferation and delayed differentiation of suprabasal keratinocytes, culminating in papillomatosis. Transcription of the Id2 gene is regulated by Myc family proteins. Moreover, Id2 is implicated as a pivotal determinant of cell fate in multiple lineages and has a demonstrated role in mediating Myc-dependent cell proliferation in vitro through its interaction with retinoblastoma protein. Using Id2 nullizygous mice, we assessed in vivo the requirement for Id2 in mediating Myc-induced papilloma formation in skin. We show that absence of Id2 has no discernible impact on any measurable attribute of Myc function or on the timing or extent of eventual tumor formation. Thus, our data argue against any essential role for Id2 in mediating Myc action in vivo.
Involvement of chemokine receptor 2 and its ligand, monocyte chemoattractant protein-1, in the development of atherosclerosis: lessons from knockout mice (2001)

Blood monocytes are the precursors of the lipid-laden foam cells that are the hallmark of early atherosclerotic lesions, but the signals that initiate their recruitment to the vessel wall are poorly understood. Here, we review in vivo studies in genetically altered mice that support the notion that monocyte chemoattractant protein-1 (a member of the chemokine family of chemotactic cytokines) and chemokine receptor 2 (its cognate receptor) play important roles in this recruitment. An unexpected finding in chemokine receptor 2-knockout mice was the diminished production of interferon-gamma, which is a potent macrophage activator. The basis of this cytokine defect is not yet clear, but suggests that chemokines may influence atherosclerotic lesion development at several levels. Understanding the roles of chemokines and cytokines in atherogenesis may provide a basis for the development of future therapeutic agents that are aimed at interrupting monocyte recruitment and activation.
Mass spectrometric characterization of a protein-ligand interaction (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMass spectrometric characterization of a protein-ligand interactionRobert J. Anderegg and David S. WagnerCite this: J. Am. Chem. Soc. 1995, 117, 4, 1374–1377Publication Date (Print):February 1, 1995Publication History Published online1 May 2002Published inissue 1 February 1995https://pubs.acs.org/doi/10.1021/ja00109a022https://doi.org/10.1021/ja00109a022research-articleACS PublicationsRequest reuse permissionsArticle Views242Altmetric-Citations48LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Biosensors based on surface concentration measuring devices — The concept of surface concentration (2007)

Surface concentration measuring devices allow direct measurement of biomolecular interactions. These devices measure the surface concentration of, for example, interacting antigens or antibodies at solid surfaces. We here exemplify the importance of using highly purified molecules together with an optimized immobilization technique for surface concentration measuring immunosensors. The immobilization of antibodies for the detection of human plasma fibronectin was compared to the reverse where the antigen was immobilized. The result was evaluated by in situ ellipsometry, an optical surface concentration measuring technique whereby the changes in polarization of light on reflection at a surface is measured. It was found that immobilized fibronectin to a much greater extent interacted with antibodies in solution as compared to the reverse situation where the antibodies were immobilized. This was explained by the multivalency of antibody binding sites on each fibronectin molecule as compared to the two antigen binding sites on each antibody. The surface concentration of fibronectin interacting with immobilized antibodies was found to depend not only on the degree of purification of the antibodies but also on the immobilization technique.
Mutational Analysis of Essential Interactions Involved in the Assembly of Hepatitis E Virus Capsid (2004)

The hepatitis E virus (HEV) capsid consists of a single structural protein, a portion of which is engaged in isosahedral contact to form a basal shell, and another portion in dimeric contact to form the homodimers protruding from the shell. Previous studies revealed that homodimers of the truncated HEV capsid proteins, E2 (amino acids 394-606) and p239 (amino acids 368-606), model dominant antigenic determinants of HEV. Immunization with these proteins protected rhesus monkeys against the virus, and three monoclonal antibodies against the homodimers could neutralize HEV infectivity and/or immune-capture of the virus. Furthermore, homodimers of p239 further interact to form particles of 23 nm diameter, rendering it an efficacious candidate vaccine. In light of this we postulate that the interactions involved in the formation of the homodimers and particles might be similar to those involved in assembly of the virus capsid. Presently, mutational analysis was carried out to identify these sites of interactions. The site of dimeric interactions was located to a cluster of six hydrophobic amino acids residues, Ala597, Val598, Ala599, Leu601, and Ala602; furthermore, the site involved in particle formation was located at amino acids 368-394. The possibility that these sites are also involved in assembly of the virus capsid is supported by the fact that they are located at two major and highly conserved hydrophobic regions of the HEV structural protein.
Development of the Double Cyclic Peptide Ligand for Antibody Purification and Protein Detection (2016)

Development of a peptide-based affinity matrix and detection reagent is important for biomedical research and the biopharmaceutical industry. In the present work, we designed and synthesized an immunoglobin G (IgG)-binding peptide ligand, Fc-III-4C. Fc-III-4C is composed of 15 residues, and the 4 cysteine residues form 2 disulfide bonds to generate a double cyclic structure. The binding affinity of the Fc-III-4C peptide toward human IgG was determined to be 2.45 nM (Kd), which is higher than that of IgG with Protein A/G (Pro-A/G). Importantly, the Fc-III-4C peptide displayed high affinity to various IgGs from different species. Fc-III-4C immobilized agarose beads exhibited high stability and reusability when compared with that of the Pro-A/G-immobilized beads. The conjugate of Fc-III-4C with FITC was demonstrated to be suitable for immunofluorescence detection of proteins expressed in cells. These results demonstrate that the Fc-III-4C peptide is a useful affinity ligand for antibody purification and as a protein detection reagent.
Mechanism of fructosamine assay: evidence against role of superoxide as intermediate in nitroblue tetrazolium reduction (1993)

We studied the chemistry of the fructosamine assay for glycated serum proteins by using the model Amadori compound N alpha-formyl-N epsilon-fructoselysine (fFL), an analog of glycated lysine residues in protein. Free lysine was formed at approximately 70% yield during a standard 20-min incubation of fFL with alkaline nitroblue tetrazolium (NBT) at 37 degrees C. Although superoxide dismutase (SOD; EC 1.15.1.1) and catalase (EC 1.11.1.6) decreased the yield of the product, monoformazan dye (MF+), the yield of MF+ was slightly greater under anaerobic than aerobic conditions, excluding a role for superoxide as an intermediate in the reduction of NBT during the fructosamine assay. SOD added to diabetic patients' sera at physiological concentrations also caused a significant (approximately 50%) inhibition of MF+ formation. This inhibition was reduced by addition of nonionic detergents, which contain organic peroxide inhibitors of SOD, to the fructosamine reagent. Overall, these data indicate that the Amadori compound is the direct reductant of NBT in the fructosamine assay and that superoxide is not an intermediate in the reaction. The inhibitory effects of SOD and catalase are most likely the result of oxygen regeneration in the assay mixture.
A High Mobility P‐Type DPP‐Thieno[3,2‐b]thiophene Copolymer for Organic Thin‐Film Transistors (2010)

A copolymer comprising 1,4-diketopyrrolo[3,4-c]pyrrole (DPP) and thieno[3,2-b]thiophene moieties, PDBT-co-TT, shows high hole mobility of up to 0.94 cm2 V−1 s−1 in organic thin-film transistors. The strong intermolecular interactions originated from π-π stacking and donor-acceptor interaction lead to the formation of interconnected polymer networks having an ordered lamellar structure, which have established highly efficient pathways for charge carrier transport.
Exon Skipping Quantification by Quantitative Reverse-Transcription Polymerase Chain Reaction in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen (2012)

Restoration of the open reading frame of the DMD gene and dystrophin protein production in Duchenne muscular dystrophy (DMD) can be achieved by exon skipping using antisense oligomers (AOs) targeted to splicing elements. Several such RNA-based gene therapy approaches are in clinical development in which all studies to date have assessed AO efficacy by semiquantitative nested reverse-transcription polymerase chain reaction (RT-PCR). Precise evaluation of dystrophin protein levels is complex and hindered by the large size and low abundance of dystrophin; thus an accurate and standardized measurement of DMD exon skipping at the RNA level remains important to assess and compare patient responses in DMD exon skipping clinical trials. Here we describe the development of a Taqman quantitative (q)RT-PCR assay to quantify exon skipping and highlight its use to determine the levels of exon skipping in DMD patients treated intramuscularly with a morpholino AO to skip exon 51, eteplirsen (AVI-4658). The muscle biopsies of these patients were previously thoroughly characterized, providing a valuable benchmark for the evaluation of novel methodology. We demonstrate that levels of dystrophin protein restoration, and thus patient response, correlate accurately with the RNA level. Furthermore, this sensitive assay detects revertant exon 51 skipped fibers in untreated biopsies, providing an important baseline to precisely quantify treatment success. This study represents the first quantitative assessment of exon skipping in a clinical trial setting. We present a standardized and reproducible method to assess patient response that will complement protein studies in future preclinical and clinical exon skipping-based gene therapy studies for DMD.
Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non–Small-Cell Lung Cancer (2010)

Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.
Intranasal atomised dexmedetomidine optimises surgical field visualisation with decreased blood loss during endoscopic sinus surgery: a randomized study (2016)

Intranasal atomised DEX resulted in improved surgical conditions with less bleeding during ESS despite the severity of the preoperative surgical lesion.
Multiobjective genetic optimization of diagnostic classifiers with implications for generating receiver operating characteristic curves (1999)

It is well understood that binary classifiers have two implicit objective functions (sensitivity and specificity) describing their performance. Traditional methods of classifier training attempt to combine these two objective functions (or two analogous class performance measures) into one so that conventional scalar optimization techniques can be utilized. This involves incorporating a priori information into the aggregation method so that the resulting performance of the classifier is satisfactory for the task at hand. We have investigated the use of a niched Pareto multiobjective genetic algorithm (GA) for classifier optimization. With niched Pareto GA's, an objective vector is optimized instead of a scalar function, eliminating the need to aggregate classification objective functions. The niched Pareto GA returns a set of optimal solutions that are equivalent in the absence of any information regarding the preferences of the objectives. The a priori knowledge that was used for aggregating the objective functions in conventional classifier training can instead be applied post-optimization to select from one of the series of solutions returned from the multiobjective genetic optimization. We have applied this technique to train a linear classifier and an artificial neural network (ANN), using simulated datasets. The performances of the solutions returned from the multiobjective genetic optimization represent a series of optimal (sensitivity, specificity) pairs, which can be thought of as operating points on a receiver operating characteristic (ROC) curve. All possible ROC curves for a given dataset and classifier are less than or equal to the ROC curve generated by the niched Pareto genetic optimization.
In vitro and in vivo characterization of a neutral boron-containing thrombin inhibitor. (1993)

Peptide boronic acid derivatives have proven to be very potent inhibitors of serine proteases with boroarginine derivatives being particularly potent thrombin inhibitors. The importance of the charged side chain of arginine has been investigated by synthesizing a derivative in which this side chain has been replaced by a neutral one. This boronic acid derivative, D-benzyloxycarbonyl (Z)-Phe-Pro-methoxypropylglycine-pinanediol (MpgC10H16), inhibited thrombin by a competitive mechanism with an inhibition constant (Ki) of 8.9 nM. In comparison to boroarginine derivatives, Z-D-Phe-Pro-boroMpgC10H16 displayed higher selectivity for thrombin over trypsin (Ki = 1.1 microM) and plasmin (Ki = 15.7 microM). Prolongation of thrombin time and activated partial thromboplastin time were observed with micromolar concentrations of Z-D-Phe-Pro-boroMpgC10H16. In a thrombin-dependent in vitro aggregation assay with human platelets, Z-D-Phe-Pro-boroMpgC10H16 inhibited aggregation with an IC50 of 85 nM. When tested in a thrombin-dependent platelet accumulation model in the rat, a bolus injection of (Z)-D-Phe-Pro-boroMpgC10H16 (0.3-3 mg/kg) inhibited platelet accumulation. Thus, the substitution of the charged guanidino group in the P1 side chain by the neutral methoxy group resulted in a potent and highly selective thrombin inhibitor with an interesting pharmacological profile with in vitro as well as in vivo models.