gebhart/patrepeval huggingface dataset:
A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects (2004)

Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 +/- 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a KDB of 81 +/- 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagon-induced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo.
Regulation of Bcl-2 Expression by HuR in HL60 Leukemia Cells and A431 Carcinoma Cells (2009)

Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the 3'-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message. Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role in stabilizing bcl-2 mRNA in HL60 cells. Here, we have identified HuR as a component of bcl-2 messenger ribonucleoprotein (mRNP) complexes. RNA coimmunoprecipitation assays showed that HuR binds to bcl-2 mRNA in vivo. We also observed an RNA-dependent coprecipitation of HuR and nucleolin, suggesting that the two proteins are present in common mRNP complexes. Moreover, nucleolin and HuR bind concurrently to bcl-2 AU-rich element (ARE) RNA in vitro, suggesting separate binding sites for these proteins on bcl-2 mRNA. Knockdown of HuR in A431 cells leads to down-regulation of bcl-2 mRNA and protein levels. Observation of a decreased ratio of bcl-2 mRNA to heterogeneous nuclear RNA in HuR knockdown cells confirmed a positive role for HuR in regulating bcl-2 stability. Recombinant HuR retards exosome-mediated decay of bcl-2 ARE RNA in extracts of HL60 cells. This supports a role for HuR in the regulation of bcl-2 mRNA stability in HL60 cells, as well as in A431 cells. Addition of nucleolin and HuR to HL60 cell extracts produced a synergistic protective effect on decay of bcl-2 ARE RNA. HuR knockdown also leads to redistribution of bcl-2 mRNA from polysomes to monosomes. Thus, HuR seems to play a positive role in both regulation of bcl-2 mRNA translation and mRNA stability.
Mutational Analysis of Circulating Tumor Cells Using a Novel Microfluidic Collection Device and qPCR Assay (2013)

Circulating tumor cells (CTCs) provide a readily accessible source of tumor material from patients with cancer. Molecular profiling of these rare cells can lead to insight on disease progression and therapeutic strategies. A critical need exists to isolate CTCs with sufficient quantity and sample integrity to adapt to conventional analytical techniques. We present a microfluidic platform (IsoFlux) that uses flow control and immunomagnetic capture to enhance CTC isolation. A novel cell retrieval mechanism ensures complete transfer of CTCs into the molecular assay. Improved sensitivity to the capture antigen was demonstrated by spike-in experiments for three cell lines of varying levels of antigen expression. We obtained spike-in recovery rates of 74%, 75%, and 85% for MDA-MB-231 (low), PC3 (middle), and SKBR3 (high) cell lines. Recovery using matched enumeration protocols and matched samples (PC3) yielded 90% and 40% recovery for the IsoFlux and CellSearch systems, respectively. In matched prostate cancer samples (N = 22), patients presenting more than four CTCs per blood draw were 95% and 36% using IsoFlux and CellSearch, respectively. An assay for detecting KRAS mutations was described along with data from patients with colorectal cancer, of which 87% presented CTCs above the assay's limit of detection (four CTCs). The CTC KRAS mutant rate was 50%, with 46% of patients displaying a CTC KRAS mutational status that differed from the previously acquired tissue biopsy data. The microfluidic system and mutation assay presented here provide a complete workflow to track oncogene mutational changes longitudinally with high success rates.
Molecular diversity of L-type calcium channels. Evidence for alternative splicing of the transcripts of three non-allelic genes (1990)

The diversity of L-type calcium channels was probed using the polymerase chain reaction and primers based on regions conserved in the L-type skeletal muscle (CaCh 1) and cardiac calcium channels (CaCh 2). Related sequences were amplified from human heart, hamster heart, rabbit heart, mouse ovary, mouse BC3H1 cells, and hamster insulin-secreting (HIT) cells. Sequencing of various clones revealed the presence of alternate splicing in gene products coding for CaCh 1, CaCh 2, and a related calcium channel. This related gene product, which we refer to as neuroendocrine or CaCh 3, is expressed in brain and endocrine cells. The diverse products can be explained by the use of alternate exons of equal size, which account for changes in amino acid composition, in combination with an alternate splice acceptor site or an exon skipping event, which produces channels of variable length. Four variants were defined for the gene 3 product, subtypes 3a, 3b, 3c, and 3d that differed in both the sequence of the third membrane spanning segment of the fourth repeat unit (IVS3) and in the size of the linker between this and the fourth membrane spanning segment (IVS4). Three CaCh 2 variants were cloned, subtypes 2a, 2c, and 2d, that are homologous to the a, c, and d variants of CaCh 3. For the skeletal muscle calcium channel only two variants were isolated. They are homologous to those of the a and c subtypes of CaCh 2 or 3, in that they differ only in the size of the IVS3 to IVS4 linker. These results demonstrate that calcium channel diversity is created by both the expression of distinct genes and the alternate splicing of these genes.
The potential for gene repair via triple helix formation (2003)

Triplex-forming oligonucleotides (TFOs) can bind to polypurine/polypyrimidine regions in DNA in a sequence-specific manner. The specificity of this binding raises the possibility of using triplex formation for directed genome modification, with the ultimate goal of repairing genetic defects in human cells. Several studies have demonstrated that treatment of mammalian cells with TFOs can provoke DNA repair and recombination, in a manner that can be exploited to introduce desired sequence changes. This review will summarize recent advances in this field while also highlighting major obstacles that remain to be overcome before the application of triplex technology to therapeutic gene repair can be achieved.
Comparative Analysis of CD8+T Cell Responses against Human Cytomegalovirus Proteins pp65 and Immediate Early 1 Shows Similarities in Precursor Frequency, Oligoclonality, and Phenotype (2002)

CD8+ T cells are key effectors of the immune response against human cytomegalovirus (HCMV). A number of HCMV-derived CD8+ T cell epitopes are known. Using epitope prediction and subsequent testing for interferon-gamma responses by the ELISPOT assay, we identified an optimal human leukocyte antigen (HLA)-A*0201-restricted CD8+ T cell epitope derived from the major immediate early 1 (IE-1) gene product. As many as one-third of HLA-A*0201-positive, HCMV-seropositive donors make responses to this peptide (residues 316-324 [VLEETSVML]), which can exceed responses against a published immunodominant pp65 epitope (residues 495-503 [NLVPMVATV]). Major histocompatibility complex peptide tetramer staining facilitated detailed phenotypic analyses and revealed populations that resemble terminally differentiated effector cells (CD57+ and CD28-), with considerable restriction in T cell receptor beta-chain variable region use. The results confirm that, although pp65 is a major target for CD8+ T cells, the IE-1 protein may itself stimulate comparable responses in some persons.
Proof linking (2000)

Although mobile code systems typically employ link-time code verifiers to protect host computers from potentially malicious code, implementation flaws in the verifiers may still leave the host system vulnerable to attack. Compounding the inherent complexity of the verification algorithms themselves, the need to support lazy, dynamic linking in mobile code systems typically leads to architectures that exhibit strong interdependencies between the loader, the verifier, and the linker. To simplify verifier construction and provide improved assurances of verifier integrity, we propose a modular architecture based on the concept of proof linking. This architecture encapsulates the verification process and removes dependencies between the loader, the verifier, and the linker. We also formally model the process of proof linking and establish properties to which correct implementations must conform. As an example, we instantiate our architecture for the problem of Java bytecode verification and assess the correctness of this instantiation. Finally, we briefly discuss alternative mobile code verification architectures enabled by the proof-linking concept.
Clinical Outcomes and Costs of Transcatheter as Compared with Surgical Closure of Patent Ductus Arteriosus (1993)

The more effective and less costly surgical procedure was superior to transcatheter placement of the occluder for closure of isolated patent ductus arteriosus. Consequently, our results do not support the wide-spread dissemination of the occluder procedure for the management of this common congenital lesion.
A 90 ns 100 K erase/program cycle megabit flash memory (2003)

An electrically erasable, reprogrammable, 90-ns 1-Mb flash memory capable of greater than 100000 erase/program cycles is described. The memory implements a command port and an internal reference voltage generator, allowing microprocessor-controlled reprogramming. The 90-ns access time results from the 95- mu A memory cell current, low resistance polysilicide word lines, advanced scaled periphery transistors, and a di/dt optimized data-out buffer. Using CMOS inputs, power dissipation is 40 mW in the active state and 20 mu W in standby. The memory electrically erases in 900 ms and programs at the rate of 10 mu s/byte. The device contains thirty-two columns of redundant elements and utilizes flash memory cells to store the address of repaired columns. The memory was fabricated on a 1- mu m double-poly n-well CMOS process. A typical cell erase/program V/sub t/ margin is shown as a function of the number of reprogramming cycles. After 100000 cycles there is still a 2.5-V program-read margin to ensure data retention. Device parameters are listed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Therapeutic advantages of medicinal herbs fermented with Lactobacillus plantarum, in topical application and its activities on atopic dermatitis (2009)

The use of herbal medicines in the therapeutic treatment of atopic dermatitis (AD) has been suggested recently. The present study examined whether selected herbal extracts fermented in Lactobacillus plantarum (FHE) possessed anti-AD properties. In addition, the study assessed the increased bioavailability of these herbal extracts both in vitro and in vivo. The data from these experiments revealed that FHE inhibited the proliferation of splenic T and B cells in a dose-dependent manner, when activated with their mitogens. Moreover, the expression of Th1/Th2 mRNA cytokines (IL-2, IL-4, IL-5, IL-13) from mouse splenocytes was inhibited severely as was cyclosporine A. Furthermore, the release of beta-hexosaminidase in RBL-2H3 mast cells was suppressed significantly. FHE also reduced the plasma level of IgE in dust mite extract-induced AD-like NC/Nga mice. More dramatic results were found in the histological changes, which were observed by hematoxylin-eosin and toluidine blue staining, as well as in the macroscopic features on dorsal lesions of AD-like NC/Nga mice. In conclusion, the results presented in this study suggest that FHE may have therapeutic advantages for the treatment of AD due to its increased immune-suppressive and increased absorptive effects, which were fortified by L. plantarum fermentation.
Isoprenoid biosynthesis via the methylerythritol phosphate pathway (2002)

The 1-deoxyxylulose 5-phosphate reductoisomerase (DXR, EC 1.1.1.267) catalyzes the conversion of 1-deoxy-d-xylulose 5-phosphate (DXP) into 2-C-methyl-d-erythritol 4-phosphate (MEP). This transformation is a two-step process involving a rearrangement of DXP into the putative intermediate 2-C-methyl-d-erythrose 4-phosphate followed by a NADPH-dependent reduction of the latter aldehyde. By using [1-(13)C]DXP as a substrate, the rearrangement of DXP into [5-(13)C]2-C-methyl-d-erythrose 4-phosphate was shown to be NADPH dependent, although it does not involve areduction step. The putative aldehyde intermediate, obtained by chemical synthesis, was converted into MEP by the DXR in the presence of NADPH and into DXP in the presence of NADP(+), indicating the reversibility of the reaction catalyzed by the DXR. This reversibility was confirmed by the conversion of MEP into DXP in the presence of NADP(+). The equilibrium was, however, largely displaced in favour of the formation of MEP. The reduction step required the presence of a divalent cation such as Mg(2+) or Mn(2+).
Lung surfactant proteins, SP-B and SP-C, alter the thermodynamic properties of phospholipid membranes: a differential calorimetry study (1993)

The ability of the low molecular weight lung surfactant-associated proteins, SP-B and SP-C, to alter the thermotropic properties of synthetic multilamellar vesicles was tested using differential scanning calorimetry (DSC). The presence of either SP-B or SP-C in dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylglycerol (DPPG) multilamellar vesicles broadened the DSC thermogram and reduced the enthalpy of transition in a concentration-dependent manner. With both proteins, the temperature at which the peak of the phase transition (Tm) was detected was shifted to a higher value. The increase in Tm caused by both proteins was greater with DPPG than DPPC. We have interpreted these results as implying the presence of a protein-perturbed domain of lipid. Both SP-B and SP-C were found to influence the surface activity of the phospholipids in a concentration-dependent fashion. We speculate that instability of lipid packing predicted to occur at protein-created lipid domain boundaries may be important for the expression of surface activity in pulmonary surfactant.
Reversal of Multidrug Resistance in Cancer (1993)

Preface (J.A. Kellen). The Phenomenon of Multidrug Resistance (J.A. Kellen). Collateral Sensitization in Multidrug Resistance (J.L. Biedler and B.A. Spengler). Cytogenetics of Multidrug Resistance (R. Ganapathi, D. Grabowski, and G. Hoeltge). Mathematical Models of Multidrug Resistance (J. Goldie, A.J. Coldman, and A. Lai). Multidrug Resistance in Human Malignancies (J.A. Kellen). Reversal of Multidrug Resistance (D. Fan, P.J. Beltran, and C.A. O'Brian). Outlook (J.A. Kellen and D. Fan). Conclusion (J.A. Kellen). Index.
Reactivity‐based One‐pot Synthesis of Immunosuppressive Glycolipids from the Caribbean Sponge Plakortis simplex (2009)

Abstract The first synthesis of three natural glycolipid simplexides 1a – 1c , which were isolated from the marine sponge Plakortis simplex and claimed to inhibit T cell proliferation, has been concisely accomplished by a reactivity‐based one‐pot synthetic strategy under the use of p ‐toluenethioglycoside (STol) donors.
ERADicate ER Stress or Die Trying (2007)

Stress within the endoplasmic reticulum (ER) induces a sophisticated network of pathways termed the unfolded protein response (UPR), which is mediated through the ER transmembrane sensors PERK, ATF6, and IRE1. The UPR coordinates the temporary downregulation of protein translation, the upregulation of ER chaperones and folding machinery, and the enhanced expression of components necessary for ER-associated degradation (ERAD) essential for decreasing ER stress by clearing terminally misfolded proteins from the ER. Repetitive but futile folding attempts not only prolong ER stress but can also result in reactive oxygen species (ROS) generation, both of which may result in cell death. Additional mechanisms for decreasing stress and the protein load in the ER have been recently revealed. They include a newly identified function of IRE1 in degradation of select secretory protein mRNAs, a "preemptive" quality control responsible for averting translocation of select secretory proteins into the ER, upregulation of forward trafficking to allow misfolded proteins with intact exit signals to exit the ER, and upregulation of autophagy. The saturation or failure of some or all of these mechanisms can result in cell death and disease, including diabetes and a number of late-onset neurologic diseases.
Effect of Disorder on the Optically Amplified Photocatalytic Efficiency of Titania Inverse Opals (2007)

Optically amplified photochemistry with slow photons has been realized in our previous work when a photoactive material such as TiO(2) was molded into a photonic crystal and the corresponding energy of photonic bands overlapped with the electronic excitation. While numerous applications of photonic crystals have been proposed, the real practicality depends on the extent of structural imperfection that can be tolerated before significant deterioration in the optical response deems it unrealistic to use. As a result, it is important to evaluate the amount of structural disorder that can be tolerated in inverse TiO(2) opals if they are to be used as amplified photocatalysts for photolytic degradation of organics in environmental remediation and water purification. We present a systematic study on the effect of disorder with relation to the photocatalytic efficiency of oxidizing methylene blue dye adsorbed on inverse TiO(2) opals by introducing different fractions and sizes of guest spheres into the opal template. Our results show that half of the enhancement originally achieved by the inverse opal made from monodispersed 150-nm spheres is conserved when the domain size of the host spheres remains above a critical threshold. The substitution fraction can be as high as 0.4 when the guest spheres are 1.2 times larger than the host spheres. Such a high tolerance to structural disorder provides strong support for the potential use of inverse TiO(2) opals in environmental cleanup and water treatment applications.
Ultrastructural immunocytochemical analysis of elastin in the human lamina cribrosa. Changes in elastic fibers in primary open-angle glaucoma. (1992)

The elastic fiber consists of several components: a central core of alpha-elastin and a microfibrillar sheath containing three components: fibrillin, microfibril-associated glycoprotein, and a 35-kD protein with amine oxidase activity. Elastin is a major component of the elastic fibers of the extracellular matrix (ECM) of the lamina cribrosa, and elastic fibers undergo marked changes in primary open-angle glaucoma (POAG). These changes, as demonstrated previously, include loss and fragmentation of elastic fibers at the bottom of the glaucomatous cup and disorganization in the peripheral walls of the cup. The author characterized the changes in elastic fibers with age and in POAG at the ultrastructural level, using colloidal gold immunostaining and anti-human alpha-elastin antibody. In fetal eyes, there was no detectable elastin in the ECM of the lamina cribrosa. In infant eyes, elastin was present in microfibrillar aggregates in the core of the plates. In young adults, thin elastic fibers were present that ran longitudinally in the core of the plates. With age, elastic fibers become thicker, tubular, and surrounded by densely packed collagen fibers. In mild POAG, tubular elastic fibers no longer were identifiable. Fragments of elastic fibers and microfibrillar aggregates stained positively for elastin suggested new synthesis of elastin that was not organized into tubular elastic fibers. In advanced POAG, masses of nonfibrillar elastin-positive material had a spotted appearance. Throughout the cribriform plates, there was a loss of collagen fibers, proliferation of basement membranes, and bundles of elastin-negative microfibrils not associated with collagen or elastic fibers. The progression of marked changes in elastic fibers and the disorganization of the ECM of the lamina cribrosa was associated with the loss of function and continuous remodeling of the optic nerve head in POAG.
Photochemistry and Photophysics of Halogen-Substituted Dibenzothiophene Oxides1 (2004)

Dibenzothiophene-5-oxide (DBTO) cleanly produces dibenzothiophene (DBT) on direct photolysis, but with very low quantum yield. A proposed mechanism involves scission of the S-O bond which is coupled to an intersystem crossing step, thus producing the sulfide and O((3)P) via a unimolecular pathway. To test this hypothesis, heavy atom substituted DBTOs were prepared and photolyzed. Iodo-, bromo-, and chloro-substituted DBTOs show higher quantum yields for deoxygenation than does the parent molecule, in the order consistent with an intersystem crossing-related heavy atom effect. 2-Iododibenzothiophene also undergoes photochemical deiodination. Phosphorescence data are consistent with heavy-atom assisted intersystem crossing.