gebhart/patrepeval huggingface dataset:
Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy (2007)

After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance. Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure-activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial efflux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition. Recent studies of pump-substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the efflux mechanisms and, finally, may result in a clinically useful molecule.
Response of Canola Cultivars to Sclerotinia sclerotiorum in Controlled and Field Environments (2006)

Sclerotinia stem rot (SSR), caused by Sclerotinia sclerotiorum, can be a devastating disease of canola (Brassica napus) in the northern United States. No canola cultivars are marketed as having resistance to SSR. Field trials were established in Red Lake Falls, MN (2001, 2003, and 2004) and Carrington, ND (2001, 2002, 2003, and 2004) to evaluate canola cultivars for resistance to SSR. These cultivars also were evaluated for resistance to SSR under controlled conditions using the following methods: petiole inoculation technique (PIT), detached leaf assay (DLA), and oxalic acid assay (OAA). Significant (P ≤ 0.05) differences were detected among cultivars for SSR and yield in the field trials, with SSR levels varying from low to high among years and locations. Cultivars with consistent high levels and low levels of SSR in the field trials were identified. Significant (P ≤ 0.05) differences were detected among cultivars for SSR using the PIT and OAA methods, but not the DLA method. No significant (P ≤ 0.05) correlations between SSR levels in the controlled studies with SSR levels in the field trials were detected; however, significant negative correlations were detected between SSR area under the disease process curve values from the PIT method and yield from Carrington, ND in 2001 and 2002. Although the PIT and OAA methods differentiated cultivars, neither method was able to predict the reaction of cultivars to SSR in the field, indicating that field screening for SSR resistance is still critical for the development of resistant cultivars.
Intrinsic Resistance Switching in Amorphous Silicon Suboxides: The Role of Columnar Microstructure (2017)

We studied intrinsic resistance switching behaviour in sputter-deposited amorphous silicon suboxide (a-SiO <sub>x</sub> ) films with varying degrees of roughness at the oxide-electrode interface. By combining electrical probing measurements, atomic force microscopy (AFM), and scanning transmission electron microscopy (STEM), we observe that devices with rougher oxide-electrode interfaces exhibit lower electroforming voltages and more reliable switching behaviour. We show that rougher interfaces are consistent with enhanced columnar microstructure in the oxide layer. Our results suggest that columnar microstructure in the oxide will be a key factor to consider for the optimization of future SiOx-based resistance random access memory.
Steroid receptor induction of gene transcription: A two-step model (1997)

Coactivators, such as steroid receptor coactivator 1 (SRC-1A) and CREB (cAMP response element binding protein)-binding protein (CBP), are required for efficient steroid receptor transactivation. Using an in vitro transcription assay, we found that progesterone receptor (PR)-driven transcription is inhibited by a dominant negative PR ligand-binding domain-interacting region of SRC-1A, indicating that SRC-1A is required for actual transcriptional processes. In addition, these coactivators also possess intrinsic histone acetyltransferase (HAT) activity and bind to each other and another HAT, p300/CBP-associated factor. Here we show that the human PR also interacts with p300/CBP-associated factor in vitro. Recruitment of multiple HATs to target promoters suggests an important role for chromatin remodeling in transcriptional activation of genes by steroid receptors. In transient transfection assays, we found that addition of a histone deacetylase inhibitor, trichostatin A, strongly potentiated PR-driven transcription. In contrast, directing histone deacetylase-1 (HD1) to a promoter using the GAL4 DNA binding domain inhibited transcription. Furthermore, PR transactivation was repressed by recruiting HD1 into the PR-DNA complex by fusing HD1 to a PR ligand-binding domain-interacting portion of SRC-1. Collectively, these results suggest that targeted histone acetylation by recruited HAT cofactors and histone deacetylation are important factors affecting PR transactivation. Recruitment of coactivators and HATs by the liganded PR in vivo may result in (i) remodeling of transcriptionally repressed chromatin to facilitate assembly and (ii) enhanced stabilization of the preinitiation complex by the activation functions of coactivators and the liganded PR itself.
Design, Synthesis, and Validation of a β-Turn Mimetic Library Targeting Protein–Protein and Peptide–Receptor Interactions (2011)

The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring β-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 × 20 × 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 × 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from the studies is that the phenol of Tyr in endogenous ligands bearing the H-Tyr-Pro-Trp/Phe-Phe-NH(2) β-turn is important for MOR binding but may not be important for KOR (accommodated, but not preferred) and that the resulting selectivity for KOR observed with its removal can be increased by replacing the phenol OH with a chlorine substituent, further enhancing KOR affinity.
Site‐Specific Protein Modification on Living Cells Catalyzed by Sortase (2008)

The use of enzymes is a promising approach for site-specific protein modification on living cells owing to their substrate specificity. Herein we describe a general strategy for the site-specific modification of cell surface proteins with synthetic molecules by using Sortase, a transpeptidase from Staphylococcus aureus. The short peptide tag LPETGG is genetically introduced to the C terminus of the target protein, expressed on the cell surface. Subsequent addition of Sortase and an N-terminal triglycine-containing probe results in the site-specific labeling of the tagged protein. We were successful in the C-terminal-specific labeling of osteoclast differentiation factor (ODF) with a biotin- or fluorophore-containing short peptide on the living cell surface. The labeling reaction occurred efficiently in serum-containing medium, as well as serum-free medium or PBS. The labeled products were detected after incubation for 5 min. In addition, site-specific protein-protein conjugation was successfully demonstrated on a living cell surface by the Sortase-catalyzed reaction. This strategy provides a powerful tool for cell biology and cell surface engineering.
Therapeutic antibodies directed at G protein-coupled receptors (2010)

G protein-coupled receptors (GPCRs) are one of the most important classes of targets for small molecule drug discovery, but many current GPCRs of interest are proving intractable to small molecule discovery and may be better approached with bio-therapeutics. GPCRs are implicated in a wide variety of diseases where antibody therapeutics are currently used. These include inflammatory diseases such as rheumatoid arthritis and Crohn disease, as well as metabolic disease and cancer. Raising antibodies to GPCRs has been difficult due to problems in obtaining suitable antigen because GPCRs are often expressed at low levels in cells and are very unstable when purified. A number of new developments in over-expressing receptors, as well as formulating stable pure protein, are contributing to the growing interest in targeting GPCRs with antibodies. This review discusses the opportunities for targeting GPCRs with antibodies using these approaches and describes the therapeutic antibodies that are currently in clinical development.
Differential recognition of the type I interferon receptor by interferons tau and alpha is responsible for their disparate cytotoxicities. (1995)

Interferon tau (IFN tau), originally identified as a pregnancy recognition hormone, is a type I interferon that is related to the various IFN alpha species (IFN alpha s). Ovine IFN tau has antiviral activity similar to that of human IFN alpha A on the Madin-Darby bovine kidney (MDBK) cell line and is equally effective in inhibiting cell proliferation. In this study, IFN tau was found to differ from IFN alpha A in that is was > 30-fold less toxic to MDBK cells at high concentrations. Excess IFN tau did not block the cytotoxicity of IFN alpha A on MDBK cells, suggesting that these two type I IFNs recognize the type I IFN receptor differently on these cells. In direct binding studies, 125I-IFN tau had a Kd of 3.90 x 10(-10) M for receptor on MDBK cells, whereas that of 125I-IFN alpha A was 4.45 x 10(-11) M. Consistent with the higher binding affinity, IFN alpha A was severalfold more effective than IFN tau in competitive binding against 125I-IFN tau to receptor on MDBK cells. Paradoxically, the two IFNs had similar specific antiviral activities on MDBK cells. However, maximal IFN antiviral activity required only fractional occupancy of receptors, whereas toxicity was associated with maximal receptor occupancy. Hence, IFN alpha A, with the higher binding affinity, was more toxic than IFN tau. The IFNs were similar in inducing the specific phosphorylation of the type I receptor-associated tyrosine kinase Tyk2, and the transcription factors Stat1 alpha and Stat2, suggesting that phosphorylation of these signal transduction proteins is not involved in the cellular toxicity associated with type I IFNs. Experiments using synthetic peptides suggest that differences in the interaction at the N terminal of IFN tau and IFN alpha with the type I receptor complex contribute significantly to differences in high-affinity equilibrium binding of these molecules. It is postulated that such a differential recognition of the receptor is responsible for the similar antiviral but different cytotoxic effects of these IFNs. Moreover, these data imply that receptors are "spare'' with respect to certain biological properties, and we speculate that IFNs may induce a concentration-dependent selective association of receptor subunits.
The Effect of Hyaluronan Hydrogel on Fat Graft Survival (2012)

When mixed with fat, hyaluronan hydrogel can improve early fat graft survival and may enhance vascularity and prolong volume maintenance.
Cnvlutin2: Ineffectual-Activation-and-Weight-Free Deep Neural Network Computing (2017)

We discuss several modifications and extensions over the previous proposed Cnvlutin (CNV) accelerator for convolutional and fully-connected layers of Deep Learning Network. We first describe different encodings of the activations that are deemed ineffectual. The encodings have different memory overhead and energy characteristics. We propose using a level of indirection when accessing activations from memory to reduce their memory footprint by storing only the effectual activations. We also present a modified organization that detects the activations that are deemed as ineffectual while fetching them from memory. This is different than the original design that instead detected them at the output of the preceding layer. Finally, we present an extended CNV that can also skip ineffectual weights.
A critical evaluation of a specific radioimmunoassay for prostatic acid phosphatase (1982)

A radioimmunoassay (RIA) method for acid phosphatase detection was compared to a standard enzyme assay using sera from 210 normal volunteers and 285 patients with prostatic disease. Statistical and clinical comparisons were made between defined subgroups. All 55 normal females had RIA detectable serum acid phosphatase, implying that this assay cannot be entirely specific for enzyme of prostatic origin. Urinary catheterization did not affect acid phosphatase levels. In all stages of carcinoma there were more acid phosphatase elevations by the RIA method than enzyme method, but neither assay could differentiate intracapsular cancer from benign prostatic hyperplasia. A small number of patients with biopsy proven negative nodules had marginally elevated values, suggesting as obligation for closer follow-up. The RIA method may be superior for monitoring patients with more advanced malignancy. Additional practical advantages of the RIA include relative simplicity and elimination of the special serum handling required for the enzyme assay.
Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator (2007)

B136 A 30,000 compound library was screened using a p53-activation cell-based assay. To date, 2 hit compounds from this screen have proven activity in animal models. Here we focus on one of these hits, tenovin-1, along with its more water-soluble analogue, tenovin-6. Via a yeast genetic screen, biochemical assays and validation studies in mammalian cells we demonstrate that tenovins act through inhibition of the protein-deacetylase activities of SirT1 and SirT2 sirtuin family members. Tenovins are significantly more potent in mammalian cells than sirtuin inhibitors discovered using other approaches, decrease tumor growth in vivo as single agents and have led to the finding that wild-type and mutant p53 differ in their acetylation status. This study shows that using p53 as a sensor for compound activity in cells and exploiting the vast amount of available information on p53 regulation, rapidly leads to the discovery of small-molecule tools with potential as therapeutics.
Increased integrity of circulating cell-free DNA in plasma of patients with acute leukemia (2010)

Our preliminary data suggest that plasma DNA integrity is increased in acute leukemia and may be a potential biomarker for monitoring MRD. However, more work is needed.
Development of a Bioactive Paper Sensor for Detection of Neurotoxins Using Piezoelectric Inkjet Printing of Sol−Gel-Derived Bioinks (2009)

There is an increasing interest in new strategies to rapidly detect analytes of clinical and environmental interest without the need for sophisticated instrumentation. As an example, the detection of acetylcholinesterase (AChE) inhibitors such as neurotoxins and organophosphates has implications for neuroscience, drug assessment, pharmaceutical development, and environmental monitoring. Functionalization of surfaces with multiple reagents, including enzymes and chromogenic reagents, is a critical component for the effective development of "dipstick" or lateral flow biosensors. Herein, we describe a novel paper-based solid-phase biosensor that utilizes piezoelectric inkjet printing of biocompatible, enzyme-doped, sol-gel-based inks to create colorimetric sensor strips. For this purpose, polyvinylamine (PVAm, which captures anionic agents) was first printed and then AChE was overprinted by sandwiching the enzyme within two layers of biocompatible sol-gel-derived silica on paper. AChE inhibitors, including paraoxon and aflatoxin B1, were detected successfully using this sensor by measuring the residual activity of AChE on paper, using Ellman's colorimetric assay, with capture of the 5-thio-2-nitrobenzoate (TNB(-)) product on the PVAm layer. The assay provided good detection limits (paraoxon, approximately 100 nM; aflatoxin B1, approximately 30 nM) and rapid response times (<5 min). Detection could be achieved either by eye or using a digital camera and image analysis software, avoiding the need for expensive and sophisticated instrumentation. We demonstrate that the bioactive paper strip can be used either as a dipstick or a lateral flow-based biosensor. The use of sol-gel-based entrapment produced a sensor that retained enzyme activity and gave reproducible results after storage at 4 degrees C for at least 60 days, making the system suitable for storage and use in the field.
Dairy Technology (1999)

Describes the efficient transformation of milk into a variety of products, focusing on the changes in raw material, and intermediate and final products, as well as the interactions between products and processing equipment. The book details the procedures for ensuring processing efficiency and product quality.
Next-Generation Sequencing Technology Reveals a Characteristic Pattern of Molecular Mutations in 72.8% of Chronic Myelomonocytic Leukemia by Detecting Frequent Alterations in TET2, CBL, RAS, and RUNX1 (2010)

The number of molecular markers used to categorize myeloid neoplasms is constantly increasing. Here, NGS screening has been demonstrated to support a comprehensive characterization of the molecular background in CMML. A pattern of molecular mutations translates into different biologic and prognostic categories of CMML.
Trust and protection in the Illinois browser operating system (2010)

Current web browsers are complex, have enormous trusted computing bases, and provide attackers with easy access to modern computer systems. In this paper we introduce the Illinois Browser Operating System (IBOS), a new operating system and a new browser that reduces the trusted computing base for web browsers. In our architecture we expose browser-level abstractions at the lowest software layer, enabling us to remove almost all traditional OS components and services from our trusted computing base by mapping browser abstractions to hardware abstractions directly. We show that this architecture is flexible enough to enable new browser security policies, can still support traditional applications, and adds little overhead to the overall browsing experience.
Formulation and evaluation of an oral melanoma vaccine (2007)

The purpose of this study was to formulate and evaluate the physicochemical properties and efficacy of an oral melanoma vaccine. Blood, feces and vaginal wash were collected weekly and analysed by ELISA. The mortality and diameter of the tumors were determined using a vernier caliper. The oral melanoma vaccine microparticles demonstrated desirable particle size, product yield, and zeta potentials. In addition, FT-IR and DSC studies revealed that there was no significant degradation in microencapsulated extra-cellular antigen (ECA). The oral vaccine group showed 25% greater survival rate compared to the control in the efficacy and challenge studies.
Protonation State and Structural Changes of the Tetrapyrrole Chromophore during the Pr→ PfrPhototransformation of Phytochrome:  A Resonance Raman Spectroscopic Study (1999)

The photoconversion of phytochrome (phytochrome A from Avena satina) from the inactive (Pr) to the physiologically active form (Pfr) was studied by near-infrared Fourier transform resonance Raman spectroscopy at cryogenic temperatures, which allow us to trap the intermediate states. Nondeuterated and deuterated buffer solutions were used to determine the effect of H/D exchange on the resonance Raman spectra. For the first time, reliable spectra of the "bleached" intermediates meta-R(A) and meta-R(C) were obtained. The vibrational bands in the region 1300-1700 cm(-)(1), which is particularly indicative of structural changes in tetrapyrroles, were assigned on the basis of recent calculations of the Raman spectra of the chromophore in C-phycocyanin and model compounds [Kneip, C., Hildebrandt, P., Németh, K., Mark, F., Schaffner, K. (1999) Chem. Phys. Lett. 311, 479-485]. The experimental resonance Raman spectra Pr are compatible with the Raman spectra calculated for the protonated ZZZasa configuration, which hence is suggested to be the chromophore structure in this parent state of phytochrome. Furthermore, marker bands could be identified that are of high diagnostic value for monitoring structural changes in individual parts of the chromophore. Specifically, it could be shown that not only in the parent states Pr and Pfr but also in all intermediates the chromophore is protonated at the pyrroleninic nitrogen. The spectral changes observed for lumi-R confirm the view that the photoreaction of Pr is a Z --> E isomerization of the CD methine bridge. The subsequent thermal decay reaction to meta-R(A) includes relaxations of the CD methine bridge double bond, whereas the formation of meta-R(C) is accompanied by structural adaptations of the pyrrole rings B and C in the protein pocket. The far-reaching similarities between the chromophores of meta-R(A) and Pfr suggest that in the step meta-R(A) --> Pfr the ultimate structural changes of the protein matrix occur.
Plasmid Transformation of Bacillus sphaericus 1593 (1984)

Plasmids pUB110 and pBC16 were introduced by protoplast transformation into the entomocidal bacterium Bacillus sphaericus 1593. Transformants expressed the antibiotic resistance determinants present on the plasmid and exhibited sporulation frequencies and larvicidal toxicities which were equivalent to those characteristic of the parent strain. These transformations constitute the first report of genetic transfer in B. sphaericus.