gebhart/patrepeval huggingface dataset:
Identification of Fos target genes by the use of selective induction systems (1992)

c-Fos is a major component of the transcription factor AP-1 which has been implicated in the control of cell proliferation and differentiation as well as in transformation. In order to identify Fos target genes involved in these processes, we have taken advantage of the regulatory properties of the hormone-binding domain of the human estrogen receptor to develop transcriptional and post-translational induction systems, both of which allow selective elevation of Fos activity within a cell. Using this approach we have searched for Fos-responsive genes in rat fibroblasts and PC12 cells. Here we describe the identification and regulation of five Fos-responsive genes encoding a transcription factor (Fra-1), a secreted protein (Fit-1), a biosynthetic enzyme (ODC) and two membrane-associated proteins (annexin II and V), respectively. The post-translational induction system was also used to study the Fos-mediated block of neuronal differentiation of PC12 cells. These experiments demonstrate that Fos activity is dominant over NGF function and interferes with the expression of late NGF-inducible genes.
PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis (2004)

The nuclear receptor superfamily is composed of transcription factors that positively and negatively regulate gene expression in response to the binding of a diverse array of lipid-derived hormones and metabolites. Intense efforts are currently being directed at defining the biological roles and mechanisms of action of liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). LXRs have been found to play essential roles in the regulation of whole body cholesterol absorption and excretion, in the efflux of cholesterol from peripheral cells, and in the biosynthesis and metabolism of very low density lipoproteins. PPARs have been found to regulate diverse aspects of lipid metabolism, including fatty acid oxidation, fat cell development, lipoprotein metabolism, and glucose homeostasis. Intervention studies indicate that activation of PPARalpha, PPARgamma, and LXRs by specific synthetic ligands can inhibit the development of atherosclerosis in animal models. Here, we review recent studies that provide new insights into the mechanisms by which these subclasses of nuclear receptors act to systemically influence lipid and glucose metabolism and regulate gene expression within the artery wall.
Retinoic acid and interferon in human cancer: mechanistic and clinical studies. (1994)

Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid-tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction.
The Aspergillus fumigatus Sialidase Is a 3-Deoxy-d-glycero-d-galacto-2-nonulosonic Acid Hydrolase (KDNase) (2011)

Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-Å resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-D-glycero-D-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-Å resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-Å resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase.
glh-1, a germ-line putative RNA helicase from Caenorhabditis, has four zinc fingers. (1993)

We have cloned a family of putative RNA helicases from the free-living nematode Caenorhabditis elegans. One of these, a cDNA that we call glh-1, most closely matches in sequence and expression the previously described germ-line helicases PL10 from mouse and vasa from Drosophila. The amino terminus of the predicted protein of glh-1 contains a set of glycine-rich repeats similar in location and sequence to those in the predicted vasa protein. However, unlike all other putative RNA helicases, glh-1 also contains four retroviral-type zinc fingers. The RNA expression pattern of this Caenorhabditis helicase correlates with the presence of germ-line tissue in the parasitic nematode Ascaris lumbricoides var. suum and with the presence of germ cells in wild type and several germ-line mutants of Caenorhabditis. In the germ-line mutants glp-4 and glp-1, additional larger species of glh-1 RNA exist, which correspond to different adenylylated forms of the glh-1 transcript; these may be specified by motifs in the 3' untranslated region of glh-1 that are similar to adenylylation control elements and nos response elements.
Differences in the Substrate Specificities and Active-Site Structures of Two α-L-Fucosidases (Glycoside Hydrolase Family 29) fromBacteroides thetaiotaomicron (2012)

Recent studies suggest that α-L-fucosidases of glycoside hydrolase family 29 can be divided into two subfamilies based on substrate specificity and phylogenetic clustering. To explore the validity of this classification, we enzymatically characterized two structure-solved α-L-fucosidases representing the respective subfamilies. Differences in substrate specificities are discussed in relation to differences in active-site structures between the two enzymes.
Self glycolipids as T-cell autoantigens (1999)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by discrete areas of demyelination. An autoimmune response against components of myelin is thought to contribute to disease pathogenesis. Here we identify glycolipids as new targets recognized by T cells in multiple sclerosis patients. Circulating T cells reactive with glycolipids are more frequent in MS patients than in control donors as shown by enzyme-linked immunospot assay. They specifically recognize different types of glycolipids, such as gangliosides, sulfatide and galactosylceramide and release IFN-gamma and TNF-alpha. T cells specific for gangliosides were found to be CD8+, TCR alphabeta+, restricted by the MHC-like CD1b molecule and specific for epitopes residing in the carbohydrate moiety of gangliosides. Our findings suggest that in addition to self proteins, self glycolipids may represent potential source of autoantigens recognized by T cells in autoimmune diseases.
Deconstructing a Disease: RAR, Its Fusion Partners, and Their Roles in the Pathogenesis of Acute Promyelocytic Leukemia (1999)

I N THE LATE 1980s and early 1990s, the elucidation of the molecular basis of acute promyelocytic leukemia (APL) emerged as a paradigm for the connection between the bench and bedside. At that time, it became apparent that APL was, among the forms of acute myeloid leukemia, uniquely sensitive to all
Abrogation of Signal Transducer and Activator of Transcription 3 Reactivation after Src Kinase Inhibition Results in Synergistic Antitumor Effects (2007)

The reactivation of STAT3 during dasatinib treatment is caused by the engagement of a compensatory pathway that suppresses the antitumor effects of SFK inhibition and allows cancer cell survival. Abrogation of this pathway resulted in synergistic cytotoxicity. Given that STAT3 reactivation occurred in 14 of 15 solid tumor cell lines, dasatinib combined with Janus-activated kinase inhibitors may have widespread application in cancer treatment.
Identification of RNase 8 as a Novel Human Antimicrobial Protein (2006)

The antimicrobial activity of the human RNase A superfamily member RNase 8 was evaluated. Recombinant RNase 8 exhibited broad-spectrum microbicidal activity against potential pathogenic microorganisms (including multidrug-resistant strains) at micro- to nanomolar concentrations. Thus, RNase 8 was identified as a novel antimicrobial protein and may contribute to host defense.
Gene therapy of the brain (2004)

Many chronic neurologic diseases do not respond to small molecule therapeutics, and have no effective long-term therapy. Gene therapy offers the promise of an effective cure for both genetic and acquired brain disease. However, the limiting problem in brain gene therapy is delivery to brain followed by regulation of the expression of the transgene. Present day gene vectors do not cross the blood-brain barrier (BBB). Consequently, brain gene therapy requires craniotomy and the local injection of a viral gene vector. However, there are few brain disorders that can be effectively treated with local injection. Most applications of gene therapy require global expression in the brain of the exogenous gene, and this can only be achieved with a noninvasive delivery through the BBB--the trans-vascular route to brain. An additional consideration is the potential toxicity of all viral and nonviral approaches, which may either integrate into the host genome and cause insertional mutagenesis or cause inflammation in the brain. Nonviral, noninvasive gene therapy of the brain is now possible with the development of a new approach to targeting therapeutic genes to the brain following an IV administration. This approach utilizes genetically engineered molecular Trojan horses, which ferry the gene across the BBB and into neurons. Global and reversible expression of therapeutic genes in the human brain without surgery and without viral vectors is now possible.
The epidemiology of cervical carcinogenesis (1995)

Epidemiologic and laboratory data suggest that cervical cancer typically arises from a series of causal steps. Each step can be studied separately in the hope of better etiologic understanding and improved cancer prevention. The earliest identified etiologic step is infection of young women with specific types of venereally transmissible human papillomaviruses (HPVs). Cervical HPV infections often lead to low grade squamous intraepithelial lesions (mildly abnormal Pap smears). Human papillomavirus infections and their associated lesions are extremely common among young, sexually active women. The infections typically resolve spontaneously even at the molecular level within months to a few years. Uncommonly, HPV infections and/or low grade lesions persist and progress to high grade lesions. The risk factors for progression are mainly unknown but include HPV type and intensity, cell-mediated immunity, and reproductive factors. Nutritional factors or co-infection with other pathogens may also be involved at this apparently critical etiologic step between common low grade and uncommon high grade intraepithelial lesions. Except for advancing age, no epidemiologic risk factors have been found for the next step between high grade intraepithelial lesions and invasive cancer. At the molecular level, invasion is associated with integration of viral DNA. Based on worldwide research, the steps in cervical carcinogenesis appear to be fundamentally the same everywhere, with a central role for HPV infection. The importance of etiologic cofactors like smoking, however, may vary by region.
A SENSITIVE, PRECISE RADIOIMMUNOASSAY OF SERUM INSULIN RELYING ON CHARCOAL SEPARATION OF BOUND AND FREE HORMONE MOIETIES (1972)

ABSTRACT A radioimmunoassay method for the measurement of plasma insulin is described relying on activated charcoal for the separation of free and bound fractions. The technique illustrates the application of theoretical precepts designed to maximise assay precision in all radioimmunoassay and other saturation assay techniques. In addition, because particular emphasis has been placed on ensuring that, as far as is possible, all incubation mixtures are similar as possible other than in hormone concentration, non-specific effects appear to have been essentially eliminated. The technique yields a mean normal fasting value of 5.3μU/ml (range 2–14 μU/ml). Its sensitivity is such that 10 μl samples of serum (or plasma) may be assayed.
Optical Probes for Biological Applications Based on Surface-Enhanced Raman Scattering from Indocyanine Green on Gold Nanoparticles (2005)

We report surface-enhanced Raman scattering (SERS) studies on indocyanine green (ICG) on colloidal silver and gold and demonstrate a novel optical probe for applications in living cells. In addition to its own detection by the characteristic ICG SERS signatures, the ICG gold nanoprobe delivers spatially localized chemical information from its biological environment by employing SERS in the local optical fields of the gold nanoparticles. The probe offers the potential to increase the spectral specificity and selectivity of current chemical characterization approaches of living cells and biomaterials based on vibrational information.
Structural Basis for Membrane Anchorage of Viral ϕ29 DNA during Replication (2005)

Prokaryotic DNA replication is compartmentalized at the cellular membrane. Functional and biochemical studies showed that the Bacillus subtilis phage 29-encoded membrane protein p16.7 is directly involved in the organization of membrane-associated viral DNA replication. The structure of the functional domain of p16.7 in complex with DNA, presented here, reveals the multimerization mode of the protein and provides insights in the organization of the phage genome at the membrane of the infected cell.
Design, Synthesis, and Biological Functionality of a Dendrimer-Based Modular Drug Delivery Platform (2011)

A modular dendrimer-based drug delivery platform was designed to improve upon existing limitations in single dendrimer systems. Using this modular strategy, a biologically active platform containing receptor mediated targeting and fluorescence imaging modules was synthesized by coupling a folic acid (FA) conjugated dendrimer with a fluorescein isothiocyanate (FITC) conjugated dendrimer. The two different dendrimer modules were coupled via the 1,3-dipolar cycloaddition reaction ("click" chemistry) between an alkyne moiety on the surface of the first dendrimer and an azide moiety on the second dendrimer. Two simplified model systems were also synthesized to develop appropriate "click" reaction conditions and aid in spectroscopic assignments. Conjugates were characterized by (1)H NMR spectroscopy and NOESY. The FA-FITC modular platform was evaluated in vitro with a human epithelial cancer cell line (KB) and found to specifically target the overexpressed folic acid receptor.
Mannostatins A and B: New inhibitors of .ALPHA.-D-mannosidase, produced by Stereptoverticillium verticillus var. quintum ME3-AG3: Taxonomy, production, isolation, physico-chemical properties and biological activities. (1989)

Mannostatins have been isolated as part of a program designed to find microorganism-produced inhibitors of alpha-D-mannosidase from Streptoverticillium verticillus var. quintum. They were purified by sequential use of active carbon and Dowex resins and then isolated as colorless powders. Mannostatins A and B have the molecular formula, C6H13NO3S and C6H13NO4S, respectively. They were competitive with the substrate, and the inhibition constants (Ki) of mannostatins A and B were 4.8 x 10(-8) M.
NAP: Research and Development of a Peptide Derived from Activity-Dependent Neuroprotective Protein (ADNP) (2006)

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.
The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective (2008)

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease.
Preventing transfer of infectious agents (2015)

Xenotransplantation using pig cells, tissues and organs may be associated with the transfer of porcine infectious agents, which may infect the human recipient and in the worst case induce a disease (zoonosis). To prevent this, a broad screening program of the donor animals for putative zoonotic microorganisms, including bacteria, viruses, fungi and others, using sensitive and specific detection methods has to be performed. As long as it is still unknown, which microorganism represents a real risk for the recipient, experience from allotransplantation should be brought in. Due to the fact that pigs can be screened long before the date of transplantation, xenotransplantation will become eventually safer compared with allotransplantation. Screening and selection of animals free of potential zoonotic microorganisms, Caesarean section, vaccination and/or treatment with chemotherapeutics are the strategies of choice to obtain donor animals not transmitting microorganisms. In the case of porcine endogenous retroviruses (PERVs) which are integrated in the genome of all pigs and which cannot be eliminated this way, selection of animals with low virus expression and generation of genetically modified pigs suppressing PERV expressions may be performed.
Large‐scale identification of proteins in human salivary proteome by liquid chromatography/mass spectrometry and two‐dimensional gel electrophoresis‐mass spectrometry (2005)

Human saliva contains a large number of proteins and peptides (salivary proteome) that help maintain homeostasis in the oral cavity. Global analysis of human salivary proteome is important for understanding oral health and disease pathogenesis. In this study, large-scale identification of salivary proteins was demonstrated by using shotgun proteomics and two-dimensinal gel electrophoresis-mass spectrometry (2-DE-MS). For the shotgun approach, whole saliva proteins were prefractionated according to molecular weight. The smallest fraction, presumably containing salivary peptides, was directly separated by capillary liquid chromatography (LC). However, the large protein fractions were digested into peptides for subsequent LC separation. Separated peptides were analyzed by on-line electrospray tandem mass spectrometry (MS/MS) using a quadrupole-time of flight mass spectrometer, and the obtained spectra were automatically processed to search human protein sequence database for protein identification. Additionally, 2-DE was used to map out the proteins in whole saliva. Protein spots 105 in number were excised and in-gel digested; and the resulting peptide fragments were measured by matrix-assisted laser desorption/ionization-mass spectrometry and sequenced by LC-MS/MS for protein identification. In total, we cataloged 309 proteins from human whole saliva by using these two proteomic approaches.
Identification of differentially expressed microRNAs in human male breast cancer (2010)

Male breast cancer displays several differentially expressed microRNAs. Not all of them are shared with breast cancer biopsies from female patients indicating male breast cancer specific alterations of microRNA expression.