gebhart/patrepeval huggingface dataset:
The Inducible Nitric Oxide Synthase Inhibitor BBS-2 Prevents Acute Lung Injury in Sheep after Burn and Smoke Inhalation Injury (2003)

In this study we examined the role of inducible nitric oxide synthase (iNOS) in acute respiratory distress syndrome (ARDS) in sheep with severe combined burn and smoke inhalation injury. BBS-2, a potent and highly selective iNOS dimerization inhibitor, was used to exclude effects on the endothelial and neuronal NOS isoforms. Seven days after surgical recovery, sheep were given a burn (40% of total body surface, 3rd degree) and insufflated with cotton smoke (48 breaths, < 40 degrees C) under anesthesia. BBS-2 was provided by constant infusion at 100 microg/kg/hour, beginning 1 hour after injury. During 48 hours, control sheep developed multiple signs of ARDS. These included decreased pulmonary gas exchange, increased pulmonary edema, abnormal lung compliance, and extensive airway obstruction. These pathologies were associated with a large increase in tracheal blood flow and elevated plasma NO2-/NO3- (NOx) levels. These variables were all stable in sham animals. Treatment of injured sheep with BBS-2 attenuated the increases in tracheal blood flow and plasma NOx levels, and significantly attenuated all the pulmonary pathologies that were noted. The results provide definitive evidence that iNOS is a key mediator of pulmonary pathology in sheep with ARDS resulting from combined burn and smoke inhalation injury.
Purification of low-abundance messenger RNAs from rat liver by polysome immunoadsorption. (1982)

We have purified three low-abundance hepatic mRNAs to near homogeneity by polysome immunoadsorption. The mRNAs coding for the precursor of ornithine transcarbamoylase [carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3], the precursor of the beta-subunit of propionyl-CoA carboxylase [propionyl-CoA:carbon dioxide ligase (ADP-forming), EC 6.4.1.3], and cystathionine beta-synthase [L-serine hydro-lyase (adding homocysteine), EC 4.2.1.22], representing approximately 0.20, 0.02, and 0.015% of total hepatic mRNA, respectively, were purified 450- to 6,300-fold. We used the following steps: interaction of rat liver polysomes with an IgG fraction of monospecific antisera raised against each polypeptide; immobilization of polysome-antibody complexes on a protein A-Sepharose column; removal of the bulk of polysomes by extensive washing; dissociation of ribosomal subunits and elution of specific mRNA with EDTA; and isolation of the eluted mRNA by chromatography on an oligo(dT)-cellulose column. It seems likely that this procedure will permit isolation of other low-abundance mRNAs and subsequent cloning of their respective cDNAs.
An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M pro inhibitor (2020)

Abstract Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we present covalentizer , a computational pipeline for creating irreversible inhibitors based on complex structures of targets with known reversible binders. For each ligand, we create a custom-made focused library of covalent analogs. We use covalent docking, to dock these tailored covalent libraries and to find those that can bind covalently to a nearby cysteine while keeping some of the main interactions of the original molecule. We found ~11,000 cysteines in close proximity to a ligand across 8,386 protein-ligand complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In prospective evaluation against a panel of kinases, five out of nine predicted covalent inhibitors showed IC 50 between 155 nM - 4.2 μM. Application of the protocol to an existing SARS-CoV-1 M pro reversible inhibitor led to a new acrylamide inhibitor series with low micromolar IC 50 against SARS-CoV-2 M pro . The docking prediction was validated by 11 co-crystal structures. This is a promising lead series for COVID-19 antivirals. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.
A flexible display module for DVD and set-top box applications (1997)

This paper presents a flexible, multi-mode display module for DVD and set-top box (STB) applications. The display module features: (1) vertical/horizontal post processing for chroma upsampling and rate conversions; (2) aspect ratio conversion for displaying 16:9 or 4:3 decoded pictures on either 16:9 or 4:3 devices; (3) user programmable, window based display with half or double window resizing; (4) sub-picture mixing and OSD overlay. All these functions are supported for both interlaced and progressive picture formats for PAL as well as NTSC systems.
Instantaneous frequency decomposition: An application to spectrally sparse sounds with fast frequency modulations (2005)

Classical time-frequency analysis is based on the amplitude responses of bandpass filters, discarding phase information. Instantaneous frequency analysis, in contrast, is based on the derivatives of these phases. This method of frequency calculation is of interest for its high precision and for reasons of similarity to cochlear encoding of sound. This article describes a methodology for high resolution analysis of sparse sounds, based on instantaneous frequencies. In this method, a comparison between tonotopic and instantaneous frequency information is introduced to select filter positions that are well matched to the signal. Second, a cross-check that compares frequency estimates from neighboring channels is used to optimize filter bandwidth, and to signal the quality of the analysis. These cross-checks lead to an optimal time-frequency representation without requiring any prior information about the signal. When applied to a signal that is sufficiently sparse, the method decomposes the signal into separate time-frequency contours that are tracked with high precision. Alternatively, if the signal is spectrally too dense, neighboring channels generate inconsistent estimates-a feature that allows the method to assess its own validity in particular contexts. Similar optimization principles may be present in cochlear encoding.
3-D Depth Reconstruction from a Single Still Image (2007)

We consider the task of 3-d depth estimation from a single still image. We take a supervised learning approach to this problem, in which we begin by collecting a training set of monocular images (of unstructured indoor and outdoor environments which include forests, sidewalks, trees, buildings, etc.) and their corresponding ground-truth depthmaps. Then, we apply supervised learning to predict the value of the depthmap as a function of the image. Depth estimation is a challenging problem, since local features alone are insufficient to estimate depth at a point, and one needs to consider the global context of the image. Our model uses a hierarchical, multiscale Markov Random Field (MRF) that incorporates multiscale local- and global-image features, and models the depths and the relation between depths at different points in the image. We show that, even on unstructured scenes, our algorithm is frequently able to recover fairly accurate depthmaps. We further propose a model that incorporates both monocular cues and stereo (triangulation) cues, to obtain significantly more accurate depth estimates than is possible using either monocular or stereo cues alone.
Wide Prevalence of Heterosubtypic Broadly Neutralizing Human Anti-Influenza A Antibodies (2011)

These data--to our knowledge, for the first time--quantitatively show the presence, albeit at low levels, of two populations of heterosubtypic BnAbs against influenza A in human serum. These observations warrant further investigation to determine their origin, host polymorphism(s) that may affect their expression levels and how to boost these BnAb responses by vaccination to reach sustainable protective levels.
Utilizing Terminal Oxidants to Achieve P450‐Catalyzed Oxidation of Methane (2012)

Abstract Terminal oxidant‐supported P450 reactions alleviate the need for substrate binding to initiate catalysis by chemically generating “compound I.” This allows investigation of the innate substrate range of the enzyme active site. Using iodosylbenzene as the oxidant, CYP153A6, a medium‐chain terminal alkane hydroxylase, exhibits methanol formation in the presence of methane demonstrating that P450‐mediated methane hydroxylation is possible.
Genome Sequencing and Informatics: New Tools for Biochemical Discoveries (1998)

During the past 3 years, we have experienced a major revolution in the biological sciences resulting from a tremendous flux of information generated by genome-sequencing efforts. Our understanding of microorganisms, the metabolic processes they catalyze, the genetic apparatuses encoding cellular
Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII (2004)

Hemophilia is a bleeding disorder caused by mutations in the genes encoding coagulation Factor VIII (FVIII) or FIX. Current treatment is through intravenous infusion of the missing protein. The major complication of treatment is the development of neutralizing Ab's to the clotting factor. Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients. However, its high cost and short half-life have limited its use. Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa). We show long-term expression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine FVIIa homolog, with no evidence of thrombotic complications at these doses. These data hold promise for a potential treatment for hemophilia and other bleeding disorders.
Expression of the G glycoprotein gene of human respiratory syncytial virus in Salmonella typhimurium (1993)

The attachment protein, G, of human respiratory syncytial virus (RSV) is an M(r) 84K to 90K species which has a high content of N-linked and O-linked carbohydrates. The unglycosylated form of this protein was expressed by inserting a full-length cDNA copy of the mRNA from the A2 strain of RSV into a prokaryotic expression vector under the control of the lambda PL promoter. Salmonella typhimurium cells transformed with the G-containing plasmid synthesized a protein of M(r) 40,000 that specifically reacted with polyclonal and two neutralizing monoclonal antibodies raised against the native RSV G glycoprotein. Recombinant G protein was purified by immunoaffinity chromatography using a neutralizing monoclonal antibody. Cotton rats immunized with the recombinant G protein produced serum antibodies to the G glycoprotein that neutralized RSV in vitro. The study demonstrates that the G protein of RSV can be expressed in bacteria and that at least one neutralizing epitope is not structurally dependent on carbohydrates.
Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes (2008)

Chronic inflammatory diseases are characterized by local tissue injury caused by immunocompetent cells, in particular CD4(+) T lymphocytes, that are involved in the pathogenesis of these disorders via the production of distinctive sets of cytokines. Here, we have characterized single CD4(+) T cells that infiltrate inflamed tissue taken from patients with psoriasis, Crohn's disease, rheumatoid arthritis, or allergic asthma. Results from a cytokine production and gene profile analysis identified a population of in vivo differentiatedretinoid-related orphan receptor gamma-expressing T cells, producing high levels of IL-17, that can represent up to 30% of infiltrating T lymphocytes. Activated Th17 cells produced IL-26, TNF-alpha, lymphotoxin-beta, and IL-22. IL-17 and IL-22 concentrations secreted by tissue infiltrating Th17 cells could reach up to 100 nM and were inversely correlated with the production of Th1- and Th2-associated cytokines. In addition, tissue-infiltrating Th17 cells are also characterized by high cell surface expression of CCR6, a chemokine receptor that was not expressed by Th1 and Th2 cells, isolated from the same lesions, and by the production of CCL20/MIP3alpha, a CCR6 ligand, associated with tissue infiltration. Culture supernatants of activated Th17 cells, isolated from psoriatic lesions, induced the expression of gene products associated with inflammation and abnormal keratinocyte differentiation in an IL-17 and IL-22-dependent manner. These results show that tissue-infiltrating Th17 cells contribute to human chronic inflammatory disease via the production of several inflammatory cytokines and the creation of an environment contributing to their migration and sequestration at sites of inflammation.
A mostly digital variable-rate continuous-time ADC &#x0394;&#x03A3; modulator (2010)

A mostly digital variable-rate continuous-time ΔΣ modulator is presented with power dissipation, output sample-rate, bandwidth, and peak SNDR ranges of 8 to 17 mW, 0.5 to 1.15 GHz, 3.9 to 18 MHz, and 67 to 78 dB, respectively. The IC is implemented in a 65 nm CMOS process with an active area of 0.07 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> .
Synthesis of imidazo-fused bridgehead-nitrogen 2′-deoxyribo-C-nucleosides: coupling-elimination reactions of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid (1985)

A short synthesis of imidazo-fused bridgehead-nitrogen 2′-deoxyribo-C-nucleosides has been developed. This is based on a coupling–elimination reaction of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid with a series of aminoalkyl-substituted heterocycles and alcohols. The intermediate α,β-unsaturated carboxamides and esters thus formed are converted into novel imidazo[1,5-a]pyridine, imidazo[1,5-b]pyridazine, and imidazo[5,1-f][1,2,4]triazine 2′-deoxyribo-C-nucleosides, including analogues of 2′-deoxyguanosine and 2′-deoxyadenosine. Assignment of the anomeric configuration of the nucleosides is made on the basis of proton n.O.e. experiments.
Tissue distribution of beta 3-adrenergic receptor mRNA in man. (1993)

Expression of mRNA for beta 1-, beta 2-, and beta 3-adrenergic receptors (beta 1-, beta 2-, and beta 3-AR) was investigated in human tissues. beta 1- and beta 2-AR mRNA distribution correlated with that of the cognate receptors established by pharmacological studies. beta 3-AR transcripts were abundant in infant perirenal brown adipose tissue, characterized by the presence of uncoupling protein (UCP) mRNA. In adult whole adipose tissues, beta 3-AR mRNA levels were high in deep deposits such as perirenal and omental, and lower in subcutaneous. In these deposits, UCP mRNA levels paralleled those of beta 3-AR. However, isolated omental and subcutaneous adipose cells, enriched in white adipocytes, expressed beta 3-AR but no UCP transcripts. beta 3-AR mRNA was highly expressed in gallbladder, and to a much lower extent in colon, independently of UCP mRNA. Quadriceps or abdominal muscles, heart, liver, lung, kidney, thyroid, and lymphocytes did not express intrinsic beta 3-AR mRNA. This study demonstrates that substantial amounts of brown adipocytes exist throughout life in adipose deposits, which are generally classified as white. These deposits are the main sites of beta 3-AR expression, which also occurs in gallbladder and colon. beta 3-AR may thus be involved in the control of lipid metabolism, possibly from fat assimilation in the digestive tract, to triglyceride storage and mobilization in adipose tissues.
Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: a new target to improve endothelial function (2007)

Our data highlight a pivotal role for the receptor Mas in preserving normal vascular relaxation. Consequently, Mas agonists arise as a promising tool in the treatment of cardiovascular diseases characterized by endothelial dysfunction.
Interventions for treating oral candidiasis for patients with cancer receiving treatment (2007)

There is weak and unreliable evidence that the absorbed drug, ketoconazole, may eradicate oral candidiasis and that a higher dose of the partially absorbed drug, clotrimazole, may give greater benefit than a lower 10 mg dose, however, researchers may wish to prevent rather than treat oral candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed.
Defining and Combating the Mechanisms of Triclosan Resistance in Clinical Isolates ofStaphylococcus aureus (2002)

The MICs of triclosan for 31 clinical isolates of Staphylococcus aureus were 0.016 micro g/ml (24 strains), 1 to 2 micro g/ml (6 strains), and 0.25 micro g/ml (1 strain). All the strains for which triclosan MICs were elevated (>0.016 micro g/ml) showed three- to fivefold increases in their levels of enoyl-acyl carrier protein (ACP) reductase (FabI) production. Furthermore, strains for which triclosan MICs were 1 to 2 micro g/ml overexpressed FabI with an F204C alteration. Binding studies with radiolabeled NAD(+) demonstrated that this change prevents the formation of the stable triclosan-NAD(+)-FabI complex, and both this alteration and its overexpression contributed to achieving MICs of 1 to 2 micro g/ml for these strains. Three novel, potent inhibitors of FabI (50% inhibitory concentrations, < or =64 nM) demonstrated up to 1,000-fold better activity than triclosan against the strains for which triclosan MICs were elevated. None of the compounds tested from this series formed a stable complex with NAD(+)-FabI. Consequently, although the overexpression of wild-type FabI gave rise to an increase in the MICs, as expected, overexpression of FabI with an F204C alteration did not cause an additional increase in resistance. Therefore, this work identifies the mechanisms of triclosan resistance in S. aureus, and we present three compounds from a novel chemical series of FabI inhibitors which have excellent activities against both triclosan-resistant and -sensitive clinical isolates of S. aureus.
A DNA fragment with an alpha-phosphorothioate nucleotide at one end is asymmetrically blocked from digestion by exonuclease III and can be replicated in vivo. (1981)

2'-Deoxyadenosine 5'-O-(1-thiotriphosphate) (dATP[alpha S]) was introduced into the 3' ends of DNA restriction fragments with Escherichia coli DNA polymerase I to give phosphorothioate internucleotide linkages. Such "capped" 3' ends were found to be resistant to exonuclease III digestion. Moreover, the resistance to digestion is great enough that, under conditions used by us, just one strand of a double helix is digested by exonuclease III when a cap is placed at only one end; when digestion is carried to completion, this results in production of intact single strands. When digestion with exonuclease III is limited and is followed by S1 nuclease treatment, double-stranded DNA fragments asymmetrically shortened from just one side are produced. In this was thousands of nucleotides can be selectively removed from one end of a restriction fragment. In vitro introduction of phosphorothioate linkages into one end of a linearized replicative plasmid, followed by exonuclease III and S1 nuclease treatments, gives rise to truncated forms that, upon circularization by blunt-end ligation, transform E. coli and replicate in vivo.
MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress (2014)

MZB1 (pERp1) is a B-cell-specific and endoplasmic reticulum (ER)-localized protein implicated in antibody secretion and integrin-mediated cell adhesion. Here, we examine the role of MZB1 in vivo by conditional gene inactivation in the mouse germline and at different stages of B lymphopoiesis. Deletion of MZB1 impairs humoral immune responses and antibody secretion in plasma cells that naturally undergo ER stress. In addition, we found that experimental induction of ER stress by tunicamycin injections in mice results in a block of pro-B-cell to pre-B-cell differentiation specifically in Mzb1(-/-) mice. A similar developmental block was observed in Mzb1(fl/fl)mb1(Cre) mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin µ heavy chains (µHCs). MZB1 associates directly with the substrate-specific chaperone GRP94 (also called HSP90B1 or gp96) in an ATP-sensitive manner and is required for the interaction of GRP94 with µHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of µHCs under conditions of ER stress.
Enhancement of Allele Discrimination by Introduction of Nucleotide Mismatches into siRNA in Allele-Specific Gene Silencing by RNAi (2008)

Allele-specific gene silencing by RNA interference (RNAi) is therapeutically useful for specifically inhibiting the expression of disease-associated alleles without suppressing the expression of corresponding wild-type alleles. To realize such allele-specific RNAi (ASP-RNAi), the design and assessment of small interfering RNA (siRNA) duplexes conferring ASP-RNAi is vital; however, it is also difficult. In a previous study, we developed an assay system to assess ASP-RNAi with mutant and wild-type reporter alleles encoding the Photinus and Renilla luciferase genes. In line with experiments using the system, we realized that it is necessary and important to enhance allele discrimination between mutant and corresponding wild-type alleles. Here, we describe the improvement of ASP-RNAi against mutant alleles carrying single nucleotide variations by introducing base substitutions into siRNA sequences, where original variations are present in the central position. Artificially mismatched siRNAs or short-hairpin RNAs (shRNAs) against mutant alleles of the human Prion Protein (PRNP) gene, which appear to be associated with susceptibility to prion diseases, were examined using this assessment system. The data indicates that introduction of a one-base mismatch into the siRNAs and shRNAs was able to enhance discrimination between the mutant and wild-type alleles. Interestingly, the introduced mismatches that conferred marked improvement in ASP-RNAi, appeared to be largely present in the guide siRNA elements, corresponding to the 'seed region' of microRNAs. Due to the essential role of the 'seed region' of microRNAs in their association with target RNAs, it is conceivable that disruption of the base-pairing interactions in the corresponding seed region, as well as the central position (involved in cleavage of target RNAs), of guide siRNA elements could influence allele discrimination. In addition, we also suggest that nucleotide mismatches at the 3'-ends of sense-strand siRNA elements, which possibly increase the assembly of antisense-strand (guide) siRNAs into RNA-induced silencing complexes (RISCs), may enhance ASP-RNAi in the case of inert siRNA duplexes. Therefore, the data presented here suggest that structural modification of functional portions of an siRNA duplex by base substitution could greatly influence allele discrimination and gene silencing, thereby contributing to enhancement of ASP-RNAi.
Cancer-Associated Mutations in Endometriosis without Cancer (2017)

We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.