gebhart/patrepeval huggingface dataset:
Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase. (1983)

Five distinct acyl-CoA dehydrogenases were isolated from rat liver mitochondria using 3 5 4 0 % (NH&S04 precipitation, DEAE-Sephadex A-50 column chromatography, hydroxyapatite column chromatography, and isoelectric focusing.Sequential fractions obtained from these procedures were monitored for the various acyl-CoA dehydrogenase activities using three branched chain acyl-CoAs (isovaleryl-, 2-methylbutyryl-, and isobutyryl-CoA) and three straight chain acyl-CoAs with different chain lengths (n-butyryl-, noctanoyl-, and palmitoyl-CoA) as substrates.Two hitherto unknown dehydrogenases which are specific for branched chain acyl-CoAs were separated from the three previously known straight chain acyl-CoA dehydrogenases.These are 2-methyl branched chain acyl-CoA dehydrogenase and isovaleryl-CoA dehydrogenase.2-Methyl branched chain acyl-CoA dehydrogenase dehydrogenated 2-methylbutyryl-CoA and isobutyryl-CoA, but did not oxidize either isovaleryl-CoA or nbutyryl-CoA.Isovaleryl-CoA dehydrogenase dehydrogenated isovaleryl-CoA and n-valeryl-CoA but did not oxidize 2-methylbutyryl-CoA, isobutyryl-CoA, or n-butyryl-CoA at any significant rate.Short chain acyl-CoA, medium chain acyl-CoA, and long chain acyl-CoA dehydrogenases isolated in this manner, by close monitoring of the various acyl-CoA dehydrogenase activities in sequential fractions, had substrate specificities which were much narrower than those of the corresponding enzymes previously iso- lated.Using these isolated enzyme preparations and also crude preparations, effects of FAD addition and those of varying amounts of phenazinemethosulfate on activities of the individual enzymes were studied in order to establish the best assay conditions.The activity of all of the enzymes with an exception of short chain acyl-CoA dehydrogenase were enhanced 1.5-2.5-fold by 0.1 m M FAD addition.The affinity of FAD differed considerably from enzyme to enzyme.FAD in short chain acyl-CoA dehydrogenase was tightly bound and it was not lost during purification procedures.In contrast, medium chain acyl-CoA dehydrogenase readily lost FAD and its K , for FAD as measured by the enhancement of activity was 2.4 pM.The fractionation patterns for the five acyl-CoA dehydrogenases and properties of these five enzymes as presented here are useful as the basis for obtaining highly purified prepatutes of Health (AM 17453) and the March of Dimes (1-378).The
Brain Protection from Stroke with Intravenous TNFα Decoy Receptor-Trojan Horse Fusion Protein (2012)

Tumor necrosis factor (TNF)-α is produced in brain in response to acute cerebral ischemia, and promotes neuronal apoptosis. Biologic TNF inhibitors (TNFIs), such as the etanercept, cannot be developed as new stroke treatments because these large molecule drugs do not cross the blood-brain barrier (BBB). A BBB-penetrating biologic TNFI was engineered by fusion of the type II human TNF receptor (TNFR) to each heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as cTfRMAb-TNFR fusion protein. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse to deliver the fused TNFR across the BBB. Etanercept or the cTfRMAb-TNFR fusion protein (1 mg/kg) was administered intravenously in adult mice subjected to 1-hour reversible middle cerebral artery occlusion up to 90 minutes after the occlusion. Neuroprotection was assessed at 24 hours or 7 days after occlusion. The cTfRMAb-TNFR fusion protein treatment caused a significant 45%, 48%, 42%, and 54% reduction in hemispheric, cortical, and subcortical stroke volumes, and neural deficit, respectively. Intravenous etanercept had no therapeutic effect. Biologic TNFIs can be reengineered for BBB penetration, and the IgG-TNFR fusion protein is therapeutic after delayed intravenous administration in experimental stroke.
The RING finger protein RNF8 recruits UBC13 for lysine 63‐based self polyubiquitylation (2005)

The heterodimeric ubiquitin conjugating enzyme (E2) UBC13-UEV mediates polyubiquitylation through lysine 63 of ubiquitin (K63), rather than lysine 48 (K48). This modification does not target proteins for proteasome-dependent degradation. Searching for potential regulators of this variant polyubiquitylation we have identified four proteins, namely RNF8, KIA00675, KF1, and ZNRF2, that interact with UBC13 through their RING finger domains. These domains can recruit, in addition to UBC13, other E2s that mediate canonical (K48) polyubiquitylation. None of these RING finger proteins were known previously to recruit UBC13. For one of these proteins, RNF8, we show its activity as a ubiquitin ligase that elongates chains through either K48 or K63 of ubiquitin, and its nuclear co-localization with UBC13. Thus, our screening reveals new potential regulators of non-canonical polyubiquitylation.
Current Status of Testosterone Replacement Therapy in Men (1999)

Testosterone plays an essential role in the development of the normal male and in the maintenance of many male characteristics, including muscle mass and strength, bone mass, libido, potency, and spermatogenesis. Androgen deficiency occurs with disorders that damage the testes, including traumatic or surgical castration (primary testicular failure) or disorders in which the gonadotropin stimulation of the testes is reduced (hypogonadotropic hypogonadism). The clinical manifestations of androgen deficiency depend on the age at onset and the severity and duration of the deficiency. In adult males, these manifestations may include reduced body hair, decreased muscle mass and strength, increased fat mass, decreased hematocrit, decreased libido, erectile dysfunction, infertility, osteoporosis, and depressed mood. The forms of androgen replacement currently available in the United States are intramuscular depot injections of testosterone esters, oral tablets of testosterone derivatives, and transdermal patches. For most patients, androgen replacement therapy with testosterone is a safe, effective treatment for testosterone deficiency.
On-chip wiring for VLSI: Status and directions (1990)

The thirty-year history of silicon integrated circuits has resulted in dramatic increases in both the number of devices per chip and circuit speed. A consequence of scaling to submicron dimensions is that the major component of propagation delay will transfer from the devices to the interconnecting “wires.” Additionally, increased integration, together with scaling, leads to a need for more numerous interconnections on a chip and higher current densities. Accommodation to these changes will necessitate the use of new materials arranged in three-dimensional wiring structures which have the ability to make the most effective use of the area of the chip. Generic processing routes to achieve the desired structures are reviewed and examples are presented of two experimental structures with layers of planar wiring and vertical vias between planes. One of these integrates aluminum-alloy wiring with tungsten vias in a silicon dioxide dielectric; the other integrates copper wiring and vias in polyimide dielectric with the goal of minimizing delay due to on-chip wiring.
Cetuximab in non-melanoma skin cancer (2012)

EGFR inhibitor cetuximab is an option for recurrent or advanced SCC of skin. The combination with radiotherapy seems to be superior to cetuximab alone.
Dual action of isoprenols from herbal medicines on both PPARγ and PPARα in 3T3‐L1 adipocytes and HepG2 hepatocytes (2002)

Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARgamma but also PPARalpha as determined using the chimera assay system. These compounds also activated full-length human PPARgamma and PPARalpha in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARgamma and PPARalpha can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
The alternative open reading frame of LAGE-1 gives rise to multiple promiscuous HLA-DR-restricted epitopes recognized by T-helper 1-type tumor-reactive CD4+ T cells. (2003)

The NY-ESO-1 and LAGE-1 genes are expressed by many human cancers, but not by normal tissues, with the exception of testis and placenta. The NY-ESO-1 and LAGE-1 genes give rise to multiple MHC class I and class II-presented epitopes derived from the open reading frames (ORF) 1 and 2. Here, we have investigated whether NY-ESO-1/LAGE-1 ORF2 encodes promiscuous MHC class II-restricted epitopes. Using a set of overlapping peptides from the ORF2 protein sequence and autologous dendritic cells (DCs) from normal donors and melanoma patients, we have identified three HLA-DRB1*0401-restricted peptide sequences from the LAGE-1 ORF2 that are capable of stimulating T-helper 1-type melanoma-reactive CD4+ T cells. From these bulk CD4+ T cells, we have generated CD4+ T-cell clones able to recognize not only peptide-pulsed DCs but also autologous DCs loaded with the LAGE-1 ORF2 protein. We have demonstrated that these peptides not only bind to multiple HLA-DR molecules apart from HLA-DRB1*0401 but also stimulate CD4+ T cells when presented in the context of these HLA-DR molecules. Furthermore, our binding data have delineated two additional sequences capable of broadly binding to multiple HLA-DR molecules. Altogether, these data support the immunogenicity of NY-ESO-1/LAGE-1 ORF2 gene products and clearly demonstrate their capability to stimulate T-helper 1 type CD4+ T cells. Because of the role of these cells in promoting long-lasting antitumor CTL responses, our data provide a rationale for cancer vaccine trials with peptides derived from the NY-ESO-1/LAGE-1 ORF2 for a large fraction of patients with NY-ESO-1/LAGE-1(+) tumors.
An Efficient Heuristic Procedure for Partitioning Graphs (1970)

We consider the problem of partitioning the nodes of a graph with costs on its edges into subsets of given sizes so as to minimize the sum of the costs on all edges cut. This problem arises in several physical situations — for example, in assigning the components of electronic circuits to circuit boards to minimize the number of connections between boards. This paper presents a heuristic method for partitioning arbitrary graphs which is both effective in finding optimal partitions, and fast enough to be practical in solving large problems.
Understanding the Degree of Condensation of Phenolic and Etherified C-9 Units of in Situ Lignins (2011)

A novel approach for the quantification of the degree of condensation at the C(5) position of etherified and phenolic phenylpropane (C-9) units of in situ lignin is described. This is achieved by degrading unmethylated and methylated wood by thioacidolysis and analyzing the resultant product mixtures by quantitative (31)P NMR spectroscopy. Applying this new method to compression wood and normal wood from Pinus radiata showed that, whereas 41-47% of etherified guaiacyl C-9 units are condensed at the C(5) position, almost all phenolic guaiacyl C-9 units exist as uncondensed moieties. Analysis of milled wood lignin (MWL) isolated from the same wood by (31)P NMR spectroscopy before and after thioacidolysis showed that the phenolic guaiacyl C-9 units were more condensed than those in the in situ lignin. This is likely due to partial cleavage of the more condensed etherified linkages during the lignin isolation, leading to a relative increase in condensed phenolic guaiacyl C-9 units.
Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. (1993)

Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
Norwalk Virus Infection of Volunteers: New Insights Based on Improved Assays (1994)

Norwalk virus infection is a common cause of gastroenteritis in humans. The clinical features and virologic and immunologic responses following oral administration of Norwalk virus to 50 volunteers were monitored. New ELISAs using recombinant virus particles as the antigen source were used to assess the pattern of virus shedding and the specific immune responses. Forty-one subjects (82%) became infected; 68% were symptomatic and 32% were asymptomatic. The proportion of subjects infected was similar for those with and without preexisting antibody (82% vs. 60%; P > .2). The magnitude of seroconversion was highest in subjects who had vomiting. The peak of viral shedding was between 25 and 72 h, and virus first appeared in stool at 15 h. Specimens collected 7 days after inoculation remained positive. These results show a higher infection rate, more subclinical infections, and longer virus excretion following Norwalk virus inoculation than previously recognized.
ClaNC: point-and-click software for classifying microarrays to nearest centroids (2005)

ClaNC is freely available from http://students.washington.edu/adabney/clanc
The role of hypothermia in the management of severe brain injury: a meta-analysis. (2002)

This meta-analysis of randomized controlled trials suggests that hypothermia is not beneficial in the management of severe head injury. However, because hypothermia continues to be used to treat these injuries, additional studies are justified and urgently needed.
Equilibrium and Nonequilibrium Features in the Morphology and Structure of Physisorbed Polyelectrolyte Layers (2011)

AFM is used to characterize sodium poly(styrene sulfonate) (PSS) layers physisorbed from NaCl solutions with an ionic strength ranging between 0 and 1 M NaCl. Colloidal probe tapping mode imaging shows that domains of PSS salted brushes coexist with flatly adsorbed PSS. The brush area fraction increases with rising degree of polymerization. The surface forces (as measured with colloidal probe technique) are a superposition of steric and electrostatic forces; their respective contribution is determined by the brush area fraction. Unexpectedly, the internal properties of the brush domains (brush thickness and average chain distance) are independent of the deposition salt concentration. Both properties increase with rising polymer length/degree of polymerization, whereas only the brush thickness can be controlled by the surrounding salt concentration (equilibrium feature). Furthermore, we show that the amount of brush-like physisorbed PSS chains leads to an increase in PSS surface coverage, which is also observed with other techniques after addition of salt to the deposition solution (as is extensively described in literature).
Optimizing virtual reality for all users through gaze-contingent and adaptive focus displays (2017)

From the desktop to the laptop to the mobile device, personal computing platforms evolve over time. Moving forward, wearable computing is widely expected to be integral to consumer electronics and beyond. The primary interface between a wearable computer and a user is often a near-eye display. However, current generation near-eye displays suffer from multiple limitations: they are unable to provide fully natural visual cues and comfortable viewing experiences for all users. At their core, many of the issues with near-eye displays are caused by limitations in conventional optics. Current displays cannot reproduce the changes in focus that accompany natural vision, and they cannot support users with uncorrected refractive errors. With two prototype near-eye displays, we show how these issues can be overcome using display modes that adapt to the user via computational optics. By using focus-tunable lenses, mechanically actuated displays, and mobile gaze-tracking technology, these displays can be tailored to correct common refractive errors and provide natural focus cues by dynamically updating the system based on where a user looks in a virtual scene. Indeed, the opportunities afforded by recent advances in computational optics open up the possibility of creating a computing platform in which some users may experience better quality vision in the virtual world than in the real one.
Development of SFQ Multi-Chip Modules for Quantum Bits (2007)

We developed a multi-chip module (MCM) system of superconducting quantum bits with single-flux quantum (SFQ) interface circuits. The MCM system consists of chips with quantum bits and chips with SFQ circuits mounted on a base chip by flip-chip bonding (FCB) with superconducting solder. We report on a reliability test of the MCM system. The test was done using a resistance measurement of an MCM with 30 mum diameter bumps. Tested samples showed good durability against thermal cycles between room temperature and 4.2 K. At 4.2 K, the resistance measured through more than two hundred bumps in a series was less than 1 mOmega. Along with achieving a high reliability, reducing thermal interference from SFQ circuits to quantum bits is important. We must understand the thermal conductance between and within the chips to design a system with minimum interference. An MCM on-chip thermometer which is based on the Johnson noise thermometry, has been designed and fabricated to achieve this desired level. The preliminary results of the thermal measurement are reported.
FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L) (2004)

Abstract FLT3 (fms-like tyrosine kinase 3) is constitutively activated in about 30% of patients with acute myeloid leukemia (AML) and represents a disease-specific molecular marker. Although FLT3-LM (length mutation) and TKD (tyrosine kinase domain) mutations have been considered to be mutually exclusive, 1% to 2% of patients carry both mutations. However, the functional and clinical significance of this observation is unclear. We demonstrate that FLT3-ITD-TKD dual mutants induce drug resistance toward PTK inhibitors and cytotoxic agents in in vitro model systems. As molecular mechanisms of resistance, we found that FLT3-ITD-TKD mutants cause hyperactivation of STAT5 (signal transducer and activator of transcription-5), leading to upregulation of Bcl-x(L) and RAD51 and arrest in the G2M phase of the cell cycle. Overexpression of Bcl-x(L) was identified as the critical mediator of drug resistance and recapitulates the PTK inhibitor and daunorubicin-resistant phenotype in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor, and FLT3 PTK inhibitors restored the drug sensitivity in FLT3 dual mutant–expressing cells. Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strategies to overcome drug resistance in patients with AML.
Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. (1996)

Recently we described the molecular cloning of SLP-76, a hematopoietic cell-specific 76-kD protein that was first identified through its association with GST/Grb2 fusion proteins. The primary sequence of SLP-76 predicts a protein of 533 amino acids comprising an amino-terminal region with numerous potential tyrosine phosphorylation sites, a central region rich in proline residues, and a single carboxy-terminal SH2 domain. Here we demonstrate formally that Grb2 associates with unphosphorylated SLP-76 and map the Grb2 binding site on SLP-76 undergoes rapid tyrosine phosphorylation and associates with tyrosine phosphoproteins of 36, 62, and 130 kD. In vitro experiments show that the SH2 domain of SLP-76 associates with the 62- and 130-kD proteins and additionally with a serine/threonine kinase. Finally, we demonstrate that transient overexpression of SLP-76 results in dramatically enhanced TCR-mediated induction of nuclear factor of activated T cells (NFAT) and interleukin (IL) 2 promoter activity; and we provide evidence that a functional SLP-76 SH2 domain is required for this effect. Our data document the in vivo associations of SLP-76 with several proteins that potentially participate in T cell activation and implicate SLP-76 itself as an important molecule in TCR-mediated IL-2 production.
Gene Expression Profiles of Acute Exacerbations of Idiopathic Pulmonary Fibrosis (2009)

Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder.
Recombinant Gene Expression Protocols: Overview of Experimental Strategies for the Expression of Recombinant Genes (2003)

The direct cloning of DNA fragments, either derived from naturally occurring or artificially designed gene sequences, into various cloning vectors, including bacteriophages, plasmids, and viruses, is the cornerstone of modern molecular biology. Such recombinant constructs represent the basic reagents of molecular biology. One of the major applications utilizing cloned DNA sequences is the expression of the cloned DNA into a protein product, i.e., the expression of recombinant genes. Because the cloned DNA sequences can be modified or altered, recombinant expression technology thus enables the investigator to custom-design the final protein product to sun specific requirements. The production of such recombinant gene products is in fact one of the major success stories of modern molecular biology. Thus, in addition to answering fundamental questions related to regulation of gene expression, gene structure and function, and other basic issues of molecular biology, the technology of recombinant genes has revolutionized modern biotechnology and biomedicine. Applications in gene therapy, biopharmaceutics, biopolymers, and the like, have major impacts on science, medicine, agriculture, and industry.