gebhart/patrepeval huggingface dataset:
A Second Fatty Acid Amide Hydrolase with Variable Distribution among Placental Mammals (2006)

Fatty acid amides constitute a large and diverse class of lipid transmitters that includes the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. The magnitude and duration of fatty acid amide signaling are controlled by enzymatic hydrolysis in vivo. Fatty acid amide hydrolase (FAAH) activity in mammals has been primarily attributed to a single integral membrane enzyme of the amidase signature (AS) family. Here, we report the functional proteomic discovery of a second membrane-associated AS enzyme in humans that displays FAAH activity. The gene that encodes this second FAAH enzyme was found in multiple primate genomes, marsupials, and more distantly related vertebrates, but, remarkably, not in a number of lower placental mammals, including mouse and rat. The two human FAAH enzymes, which share 20% sequence identity and are referred to hereafter as FAAH-1 and FAAH-2, hydrolyzed primary fatty acid amide substrates (e.g. oleamide) at equivalent rates, whereas FAAH-1 exhibited much greater activity with N-acyl ethanolamines (e.g. anandamide) and N-acyl taurines. Both enzymes were sensitive to the principal classes of FAAH inhibitors synthesized to date, including O-aryl carbamates and alpha-keto heterocycles. These data coupled with the overlapping, but distinct tissue distributions of FAAH-1 and FAAH-2 suggest that these proteins may collaborate to control fatty acid amide catabolism in primates. The apparent loss of the FAAH-2 gene in some lower mammals should be taken into consideration when extrapolating genetic or pharmacological findings on the fatty acid amide signaling system across species.
Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus (1995)

Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone.
Fundamentals of balanced steady state free precession MRI (2013)

Balanced steady state free precession (balanced SSFP) has become increasingly popular for research and clinical applications, offering a very high signal-to-noise ratio and a T2 /T1 -weighted image contrast. This review article gives an overview on the basic principles of this fast imaging technique as well as possibilities for contrast modification. The first part focuses on the fundamental principles of balanced SSFP signal formation in the transient phase and in the steady state. In the second part, balanced SSFP imaging, contrast, and basic mechanisms for contrast modification are revisited and contemporary clinical applications are discussed.
Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress (2003)

Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (< 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.
Estrogen receptor–α in medial amygdala neurons regulates body weight (2015)

Estrogen receptor-α (ERα) activity in the brain prevents obesity in both males and females. However, the ERα-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded-1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERα. Specific deletion of the gene encoding ERα (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERα in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERα agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drug-mediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERα signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain.
Mutations Associated with Failure of Raltegravir Treatment Affect Integrase Sensitivity to the Inhibitor In Vitro (2008)

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3' processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7- to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3' processing was also impaired.
Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development (2015)

Natural killer T cells (NKT cells) are comprised of several subsets. However, the possible differences in their developmental mechanisms have not been fully investigated. To evaluate the dependence of some NKT subpopulations on nuclear factor-κB-inducing kinase (NIK) for their generation, we analysed the differentiation of NKT cells, dividing them into subsets in various tissues of alymphoplasia (aly/aly), a mutant mouse strain that lacks functional NIK. The results indicated that the efficient differentiation of both invariant NKT (iNKT) and non-iNKT cells relied on NIK expression in non-haematopoietic cells; however, the dependence of non-iNKT cells was lower than that of iNKT cells. Especially, the differentiation of CD8(+) non-iNKT cells was markedly resistant to the aly mutation. The proportion of two other NKT cell subsets, NK1.1(+) γδ T cells and NK1.1(-) iNKT cells, was also significantly reduced in aly/aly mice, and this defect in their development was reversed in wild-type host mice given aly/aly bone marrow cells. In exerting effector functions, NIK in NKT-αβ cells appeared dispensable, as NIK-deficient NKT-αβ cells could secrete interleukin-4 or interferon-γ and exhibit cytolytic activity at a level comparable to that of aly/+ NKT-αβ cells. Collectively, these results imply that the NIK in thymic stroma may be critically involved in the differentiation of most NKT cell subsets (although the level of NIK dependence may vary among the subsets), and also that NIK in NKT-αβ cells may be dispensable for their effector function.
Complete nucleotide sequences of the gene for human factor IX (antihemophilic factor B) (1985)

Two different human genomic DNA libraries were screened for the gene for blood coagulation factor IX by employing a cDNA for the human protein as a hybridization probe. Five overlapping lambda phages were identified that contained the gene for factor IX. The complete DNA sequence of about 38 kilobases for the gene and the adjacent 5' and 3' flanking regions was established by the dideoxy chain termination and chemical degradation methods. The gene contained about 33.5 kilobases of DNA, including seven introns and eight exons within the coding and 3' noncoding regions of the gene. The eight exons code for a prepro leader sequence and 415 amino acids that make up the mature protein circulating in plasma. The intervening sequences range in size from 188 to 9473 nucleotides and contain four Alu repetitive sequences, including one in intron A and three in intron F. A fifth Alu repetitive sequence was found immediately flanking the 3' end of the gene. A 50 base pair insert in intron A was found in a clone from one of the genomic libraries but was absent in clones from the other library. Intron A as well as the 3' noncoding region of the gene also contained alternating purine-pyrimidine sequences that provide potential left-handed helical DNA or Z-DNA structures for the gene. KpnI repetitive sequences were identified in intron D and the region flanking the 5' end of the gene. The 5' flanking region also contained a 1.9-kb HindIII subfamily repeat. The seven introns in the gene for factor IX were located in essentially the same position as the seven introns in the gene for human protein C, while the first three were found in positions identical with those in the gene for human prothrombin.
Análise não-linear geométrica de placas (2007)

Neste trabalho é apresentado um modelo para análise não-linear geométrica de placas constituídas de um material elástico linear isotrópico, através do Método dos Elementos Finitos. A formulação inclui os efeitos da deformação por corte, a possibilidade de ocorrerem grandes deslocamentos e a influência das condições de contorno no plano na resposta estática da estrutura. Aplicando-se o Princípio dos Trabalhos Virtuais, resulta um sistema de equações não-lineares de equilíbrio, que é resolvido através do Método Secante-Newton. Palavras-Chave: elementos finitos, análise não-linear, placas
Epitope mapping and structural analysis of an anti‐ErbB2 antibody A21: Molecular basis for tumor inhibitory mechanism (2007)

Anti-ErbB2 antibodies targeting distinct epitopes can have different biological functions on cancer cells. A21 prepared by surface epitope masking (SEM) method is a tumor-inhibitory anti-ErbB2 monoclonal antibody. Previously we engineered a single chain chimeric antibody chA21 with potential for therapy of ErbB2-overexpressing tumors. Here, we mapped the A21 epitope on ErbB2 extracellular domain (ECD) by screening a combinatorial phage display peptide library, serial subdomain deletion, and mutagenesis scanning. X-ray crystal structure of the A21 scFv fragment at 2.1 A resolution was also determined. A molecular model of Ag-Ab complex was then constructed based on the crystal structures of the A21 scFv and ErbB2 ECD. Some of biological functions of the A21 mAb and its derivative antibodies including their tumor cell growth inhibition and effects on the expression, internalization, and phosphorylation of ErbB2 receptor were also investigated. The results showed that A21 recognized a conformational epitope comprising a large region mostly from ErbB2 extracellular subdomain I with several surface-exposed residues important for the binding affinity. These data provide unique functional properties of A21 that are quite different from two broadly used anti-ErbB2 mAbs, Herceptin and 2C4. It suggested that the A21 epitope may be another valuable target for designing new anti-ErbB2 therapeutics.
Improved gene expression upon transfer of the adenosine deaminase minigene outside the transcriptional unit of a retroviral vector. (1989)

This study describes a type of retroviral vector called double-copy (DC) vector that was designed to improve the expression of transduced genes. The unique feature of DC vectors is that the transduced gene is inserted within the U3 region of the 3' long terminal repeat (LTR). Consequently, in the infected cell the gene is duplicated and transferred to the 5' LTR. The important result is that in its new position the gene is placed outside the retroviral transcriptional unit, eliminating or at least reducing the negative effects of the retroviral transcriptional unit. The utility of the DC vector design was tested by using a 2.1-kilobase-pair (kbp)-long adenosine deaminase (ADA; EC 3.5.4.4) minigene that was inserted into the 3' LTR of the N2 retroviral vector, generating a 2.7-kbp-long chimeric LTR. DNA blot analysis was used to show that the chimeric LTR was faithfully duplicated in cells infected with the corresponding virus, generating two copies of the ADA minigene, one copy in each LTR. Insertion of the ADA minigene into the 3' LTR of the N2 vector led to a 10- to 20-fold increase in ADA transcripts and human ADA isozyme synthesized in NIH 3T3 cells as compared to cells harboring the same vector in which the ADA minigene was inserted between the two LTRs. A similar increase in ADA expression was observed in two human lymphoid cell lines tested, HUT 78 and Raji. These results are consistent with previous observations that upstream promoters exert an inhibitory effect on promoters placed downstream and bear out the predictions used in the design of DC vectors. The use of DC vectors may contribute to the solution of the problems encountered in expressing retrovirally transduced genes in cultured cells and, in particular, when introduced into the live animal.
Direct pH Measurements by using Subcellular Targeting of 5(and 6-) Carboxyseminaphthorhodafluor in Mammalian Cells (2009)

As a means of reliably measuring intracellular pH, we have precisely targeted 5(and 6-) carboxyseminaphthorhodafluor to cellular subcompartments. This was accomplished by combining the well-established pH-sensitive dye with a protein-based reporter system. When expressed in cells, the reporter protein is designed to covalently bind ligands composed of a functional group and a reactive linker. In order to make a pH-sensitive ligand, we chemically coupled the pH sensor to a reactive linker. Several ligands of differing linker lengths were made and tested for their pH responsiveness in vitro. The most responsive of these ligands was then evaluated for its efficacy in live cell labeling and its use as an intracellular pH sensor for ratiometric confocal microscopy. Here we show that we could target this pH sensor within mammalian cells exclusively to either the nucleus or cytoplasm. Exhibiting the versatility of this reporter technology, we were also able to specifically limit pH sensor labeling to within the trafficking pathway of integrins and directly measure pH of this environment. Results correspond well with previously published reports. Both the simplicity and flexibility of the technology used in this study make possible the development of diverse targeted microenvironmental sensors or other moieties of interest.
Oxidized Low-Density Lipoproteins Inhibit Endothelial Cell Proliferation by Suppressing Basic Fibroblast Growth Factor Expression (2000)

Cytotoxic effects of ox-LDL on ECs are attributable in part to suppression of bFGF expression.
Association of 8p23 Deletions with Poor Survival in Head and Neck Cancer (2001)

Our data suggest that 8p23 allelic loss is associated with poor prognosis in head and neck squamous cell carcinoma and could be useful refining diagnosis of these tumors.
Identification of small molecule inhibitors of Zcchc11 TUTase activity (2015)

The RNA-binding protein Lin28 regulates the expression of the let-7 family of microRNAs (miRNAs) during early embryonic development. Lin28 recruits the 3' terminal uridylyl transferase (TUTase) Zcchc11 (TUT4) and/or Zcchc6 (TUT7) to precursor let-7 RNA (pre-let-7) to selectively block let-7 biogenesis. Uridylated pre-let-7 is targeted for decay by the downstream exonuclease Dis3l2 thereby preventing processing to mature let-7. Activation of this oncogenic pathway via up-regulation of Lin28 expression promotes cellular transformation, drives tumorigenesis in mouse models, and is frequently observed in a wide variety of cancer. Recent proof-of-principle experiments showed that Zcchc11 knockdown inhibits the tumorigenicity of Lin28-expressing human cancer cells and established this enzyme as a possible new therapeutic target for human malignancies. However, there are currently no known pharmacological agents capable of targeting this novel enzyme. In this study we developed and applied a sensitive biochemical assay that monitors Zcchc11 activity. Using this assay we performed an automated high-throughput screen of ∼ 15,000 chemicals to identify putative TUTase inhibitors. Several of these small molecules were validated as specific inhibitors of Zcchc11 activity. Our results demonstrate the feasibility of screening for TUTase inhibitors and present a relatively simple platform that can be exploited for future drug discovery efforts aimed at restoring let-7 expression in cancer.
Interstitial collagenase (matrix metalloproteinase-1) expresses serpinase activity. (1991)

Human endothelial cells treated with either interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate secreted a metalloproteinase that hydrolyzed and inactivated the two major serine proteinase inhibitors (Serpins) found in plasma, alpha 1-proteinase inhibitor and alpha 1-antichymotrypsin. Surprisingly, the responsible metalloproteinase was identified as human interstitial collagenase (matrix metalloproteinase-1), an enzyme whose only known physiologic substrate has heretofore been believed to be the extracellular matrix molecule, collagen. The metalloproteinase inactivated the Serpins by cleaving peptide bonds at sites unrelated to those hydrolyzed in collagenous macromolecules. NH2-terminal sequence analysis localized the cleavage sites in the Serpins to regions near their respective reactive site centers at three distinct peptide bonds on the amino-terminal side of bulky, hydrophobic residues. Together, these data indicate that matrix metalloproteinase-1 displays an expanded substrate repertoire that supports the existence of a new interface between connective tissue turnover and Serpin function.
Synthesis and Anti‐tumor Activities of Novel Pyrazolo[1,5‐a]pyrimidines (2006)

A series of novel pyrazolo[1,5-a]pyrimidines were designed and synthesized in order to find novel potent anti-tumor compounds. The structures of all the compounds were confirmed by IR, (1)H-NMR, elemental analysis, and MS. Their anti-tumor activities against cancer cell lines were tested by the MTT method in vitro. Compound 19 displayed potent anti-tumor activity.
Review of Error Resilient Coding Techniques for Real-Time Video Communications (2000)

In this paper we review error resilience techniques for real-time video transport over unreliable networks. Topics covered include an introduction to today&amp;apos;s protocol and network environments and their characteristics, encoder error resilience tools, decoder error concealment techniques, as well as techniques that require cooperation between encoder, decoder and the network. We provide a review of general principles of these techniques as well as specific implementations adopted by the H.263 and MPEG-4 video coding standards. The majority of the paper is devoted to the techniques developed for block-based hybrid coders using motion-compensated prediction and transform coding. A separate section covers error resilience techniques for shape coding in MPEG-4.
Affine structure from motion (1991)

A mobile observer samples sequences of narrow-field projections of configurations in ambient space. The so-called structure-from-motion problem is to infer the structure of these spatial configurations from the sequence of projections. For rigid transformations, a unique metrical reconstruction is known to be possible from three orthographic views of four points. However, human observers seem able to obtain much shape information from a mere pair of views, as is evident in the case of binocular stereo. Moreover, human observers seem to find little use for the information provided by additional views, even though some improvement certainly occurs. The rigidity requirement in its strict form is also relaxed. We indicate how solutions of the structure-from-motion problem can be stratified in such a way that one explicitly knows at which stages various a priori assumptions enter and specific geometrical expertise is required. An affine stage is identified at which only smooth deformation is assumed (thus no rigidity constraint is involved) and no metrical concepts are required. This stage allows one to find the spatial configuration (modulo an affinity) from two views. The addition of metrical methods allows one to find shape from two views, modulo a relief transformation (depth scaling and shear). The addition of a third view then merely serves to settle the calibration. Results of a numerical experiment are discussed.
Detection and identification of mycobacteria by amplification of rRNA (1990)

Oligonucleotides specific at a genus, group, or species level were defined by a systematic comparison of small-subunit rRNA sequences from Mycobacterium tuberculosis, M. bovis, M. africanum, M. bovis BCG, M. avium, M. kansasii, M. marinum, M. gastri, M. chelonae, M. smegmatis, M. terrae, M. nonchromogenicum, M. xenopi, M. malmoense, M. szulgai, M. scrofulaceum, M. fortuitum, M. gordonae, M. intracellulare, M. simiae, M. flavescens, M. paratuberculosis, M. sphagni, M. cookii, M. komossense, M. phlei, and M. farcinica. On the basis of the defined oligonucleotides, the polymerase chain reaction technique was explored to develop a sensitive taxon-specific detection system for mycobacteria. By using M. tuberculosis as a model system, fewer than 10 bacteria could be reliably detected by this kind of assay. These results suggest that amplification of rRNA sequences by the polymerase chain reaction may provide a highly sensitive and specific tool for the direct detection of microorganisms without the need for prior cultivation.