gebhart/patrepeval huggingface dataset:
Methanocaldococcus jannaschii Uses a Modified Mevalonate Pathway for Biosynthesis of Isopentenyl Diphosphate (2006)

Archaea have been shown to produce isoprenoids from mevalonate; however, genome analysis has failed to identify several genes in the mevalonate pathway on the basis of sequence similarity. A predicted archaeal kinase, coded for by the MJ0044 gene, was associated with other mevalonate pathway genes in the archaea and was predicted to be the "missing" phosphomevalonate kinase. The MJ0044-derived protein was tested for phosphomevalonate kinase activity and was found not to catalyze this reaction. The MJ0044 gene product was found to phosphorylate isopentenyl phosphate, generating isopentenyl diphosphate. Unlike other known kinases associated with isoprene biosynthesis, Methanocaldococcus jannaschii isopentenyl phosphate kinase is predicted to be a member of the aspartokinase superfamily.
Solubility and Kinetic Release Studies of Naproxen and Ibuprofen in Soluble Epichlorohydrin-β-cyclodextrin Polymer (2006)

Abstract Naproxen (NAP) and ibuprofen (IBU) are poor water soluble anti-inflammatory drugs. A water-soluble epichlorohydrin-β-cyclodextrin polymer (β-CDEPI) was synthesized in a highly basic aqueous solution and at a molar ratio β-CD/EPI of 1:12. Drug solubility and kinetic release of NAP and IBU from the inclusion complexes they form with β-CDEPI as host was studied. Water solubility for both drugs in the presence of this polymer increased (NAP 0.28 mmol and IBU 0.40 mmol per gram of β-CDEPI). The apparent inclusion constants for both drugs in β-CDEPI were calculated from the solubility-phase diagrams with Kincl values of 4300 ± 100 L.mol− 1 for NAP and 5100 ± 300 L.mol− 1 for IBU. Kinetic release of Ibuprofen gave a pure Fick trend (t1/2) behavior. However, for Naproxen a zero order was obtained (t). These results indicate that the nature and bulkiness of the drugs are ruling these kinetic behaviors in the environment of a highly branched polymer. Keywords: Inclusion complexCyclodextrin polymerDrug deliveryIbuprofenNaproxen
Human embryonic stem cells and their spontaneous differentiation. (2005)

Human embryonic stem cells (hESCs) usually grow in saucer-shaped colonies with thickened rims and can form spherical human embryoid bodies (hEBs) under non-adherent conditions. A problem associated with ES cell culture is the spontaneous differentiation of cells into a variety of cell types representing all three germ layers, which is evident in both hESC colonies and hEBs. This presentation deals with the precise origins of hESCs and their spontaneous differentiation in vitro. We have used advanced digital microscopy, including transmission electron microscopy (TEM) to define the fine structure of these cells. We present images of undifferentiated hESCs and their spontaneous differentiation into basic embryonic cell types such as nerve, muscle, connective tissue, epithelium, and digestive tract progenitors, representing all three primary germ layers: embryonic ectoderm, mesoderm and endoderm. It appears that hESCs work in concert and interact with one another, as in tissue formation of the embryo. Our fine structural observations agree mostly with those of the Thomson group. Digital microscopy of plastic sections and TEM are invaluable tools in the precise characterization of cells forming these tissues and a combined study with immunofluorescent markers is most desirable.
Leukocyte chemoattraction by 1,2-diacylglycerol. (1988)

Previous reports have demonstrated the hydrolysis of inositol phospholipids in polymorphonuclear leukocytes (PMN) in response to chemoattractants and in lymphocytes in response to the mitogen phytohemagglutinin. We investigated the role of 1,2-diacylglycerol, one of the products of receptor-linked phosphatidylinositol hydrolysis, in mediating the migratory response of leukocytes. In an under-agarose migration system, we found 1,2-dioctanoylglycerol to be a strong chemoattractant for human PMN, 6C3HED (a mouse thymic lymphoma), and Jurkat (a human T-cell leukemia). By using a modified Boyden chamber assay, the migratory response of PMN to 1,2-dioctanoylglycerol was determined to be primarily chemotactic. Analysis of structural analogs indicated that both the position and number of acyl chains are important in determining chemoattractant activity. These studies demonstrate that exogenous 1,2-diacylglycerol can stimulate the directed migration of leukocytes. They further suggest that the formation of 1,2-diacylglycerol following receptor-mediated stimulation may represent a common step in the migratory responses of myeloid and lymphoid cells.
Regulation of Human Immunodeficiency Virus Type 1 Infectivity by the ERK Mitogen-Activated Protein Kinase Signaling Pathway (1999)

ERK1 and ERK2 mitogen-activated protein kinases (MAPK) play a critical role in regulation of cell proliferation and differentiation in response to mitogens and other extracellular stimuli. Mitogens and cytokines that activate MAPK in T cells have been shown to activate human immunodeficiency virus type 1 (HIV-1) replication. Little is known about the signal transduction pathways that activate HIV-1 replication in T cells upon activation by extracellular stimulation. Here, we report that activation of MAPK through the Ras/Raf/MEK signaling pathway enhances the infectivity of HIV-1 virions. Virus infectivity was enhanced by treatment of cells with MAPK stimulators, such as serum and phorbol myristate acetate, as well as by coexpression of constitutively activated Ras, Raf, or MEK (MAPK kinase) in the absence of extracellular stimulation. Treatment of cells with PD 098059, a specific inhibitor of MAPK activation, or with a MAPK antisense oligonucleotide reduced the infectivity of HIV-1 virions without significantly affecting virus production or the levels of virion-associated Gag and Env proteins. MAPK has been shown to regulate HIV-1 infectivity by phosphorylating Vif (X. Yang and D. Gabuzda, J. Biol. Chem. 273:29879-29887, 1998). However, MAPK activation enhanced virus infectivity in some cells lines that do not require Vif function. The HIV-1 Rev, Tat, p17(Gag), and Nef proteins were directly phosphorylated by MAPK in vitro, suggesting that other HIV-1 proteins are potential substrates for MAPK phosphorylation. These results suggest that activation of the ERK MAPK pathway plays a role in HIV-1 replication by enhancing the infectivity of HIV-1 virions through Vif-dependent as well as Vif-independent mechanisms. MAPK activation in producer cells may contribute to the activation of HIV-1 replication when T cells are activated by mitogens and other extracellular stimuli.
Isolation and Characterization of a Protein Fraction That Binds to Enhancer Core Sequences in Intracisternal A-particle Long Terminal Repeats (1989)

The U3 region of mouse intracisternal A-particle (IAP) long terminal repeats (LTRs) contains several nuclear protein-binding domains. Two of these contain sequences with homology to the SV40 enhancer core. We refer to these two domains as Enh1 and Enh2. The Enh2 domain is an important determinant of promoter activity in vivo. We report here the isolation of nuclear fractions from human 293 and mouse MOPC-315 cells which interact with Enh1 and Enh2. Purification was achieved via DNA-affinity chromatography on a multimerized oligonucleotide representing the Enh2 region from the LTR of the mouse genomic IAP element, MIA14. Glycerol gradient sedimentation suggested a native Mr of approximately 80-100 for the binding component(s) in both crude and affinity-purified fractions. UV cross-linking showed that the binding activity involved two polypeptides within this size range. The affinity-isolated fraction from each cell line was highly purified, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and in vitro binding analysis. Exonuclease III footprinting showed that the two polypeptides interacted preferentially with the Enh1 and Enh2 domains within a 139-base pair segment from the MIA14 LTR. The polypeptides interacted in a sequence-specific manner with oligonucleotides representing these domains within the IAP LTR and with oligonucleotides containing the enhancer core sequence from SV40 and polyoma virus. Equilibrium binding studies indicated that the apparent dissociation constants for the polypeptides binding to the enhancer core sequence from MIA14, SV40, and polyoma virus were similar. Therefore, this affinity-purified fraction may represent a novel enhancer core-binding component which is distinct from the previously characterized rat CCAAT/enhancer-binding protein, C/EBP.
Finding the Right Sperm for the Job (1995)

Journal Article Finding the right sperm for the job: A technique to preselect the sex of livestock has been used successfully to sidestep a human birth defect Get access Anna Maria Gillis Anna Maria Gillis Search for other works by this author on: Oxford Academic Google Scholar BioScience, Volume 45, Issue 8, September 1995, Pages 525–526, https://doi.org/10.2307/1312695 Published: 01 September 1995
Human T Cells Armed with Her2/neu Bispecific Antibodies Divide, Are Cytotoxic, and Secrete Cytokines with Repeated Stimulation (2006)

These studies show that armed ATC are specific, durable, and highly functional T-cell populations in vitro. These previously unappreciated broad and long-term functions of armed ATC are encouraging for their therapeutic use in treating cancer.
A Multimodal Targeting Nanoparticle for Selectively Labeling T Cells (2008)

A nanoparticle system capable of selectively labeling and monitoring antigen-specific cytotoxic T lymphocytes (CTLs) by magnetic resonance imaging and fluorescence reporting is demonstrated. These targeting nanoparticles were functionalized with tumor-specific peptide-major histocompatibility complex (MHC) (see figure). TEM and fluorescence microscopy reveal nanoparticle binding to the CTL membrane.
Assessment of disease severity and prognosis. (2003)

The Subcommittee members initially agreed on the concepts of disease activity, damage and severity, defining severity as the total effect of disease on organ function. It was decided to start with the assessment of severity using the Medsger's severity scale. A revised version of this scale was constructed. The rationale for the exclusion of other variables was provided.
Identification of the Functional Promoter Regions in the Human Gene Encoding the Myosin Alkali Light Chains MLC1 and MLC3 of Fast Skeletal Muscle (1989)

The human gene encoding the alkali myosin light chains (MLC) 1 and 3 of fast skeletal muscle has been isolated. Two separate start sites for transcription have been identified by S1 analysis of muscle RNA. The nucleotide sequences of both proximal promoter regions have been determined and compared to the corresponding gene regions of other species. Several conserved promoter elements were located within 140 nucleotides upstream of the mRNA cap site, whereas further upstream no homologous sequences were found. Unidirectional 5' deletion mutants of both MLC promoters were used to direct bacterial chloramphenicol acetyltransferase activity in transient transfection assays of muscle and nonmuscle cells. Approximately 120 nucleotides of the MLC1 promoter and 80 nucleotides of the MLC3 promoter were sufficient for the transcriptional activation in primary myotubes and to a lower degree also in fibroblasts and hepatocytes. The preferential expression in muscle cells was not dependent on the conserved MLC consensus sequence, CCTTTTATAG, but it absolutely required the CCAT box or the CAT-like box in the MLC1 and MLC3 promoters, respectively. The weak activity of the MLC1 promoter was markedly enhanced in myotubes when DNA from the 3' gene flanking sequence was included in the chloramphenicol acetyltransferase constructs.
IL-17 and Therapeutic Kynurenines in Pathogenic Inflammation to Fungi (2008)

Largely viewed as proinflammatory, innate responses combine with adaptive immunity to generate the most effective form of antifungal resistance, and T cells exercise feedback control over diverse effects of inflammation on infection. Some degree of inflammation is required for protection, particularly in mucosal tissues, during the transitional response occurring between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease and ultimately prevents pathogen eradication. IDO, tryptophan catabolites ("kynurenines"), and regulatory T cells help to tame overzealous and exaggerated inflammatory responses. In this context, IL-23 and the Th17 pathway, which down-regulate tryptophan catabolism, may instead favor pathology and serve to accommodate the seemingly paradoxical association of chronic inflammation with fungal persistence. Recent data support a view in which IL-23/IL-17 antagonistic strategies, including the administration of synthetic kynurenines, could represent a new means of harnessing progressive or potentially harmful inflammation.
High-resolution whole-heart 3D T2 mapping can assess tissue heterogeneity of chronic MI in swine (2015)

Background Remodeling of myocardium after infarction (MI) is linked to ventricular arrhythmias. [1] It has been demonstrated that the presence of scar containing isthmuses of viable myocardium resulting in a heterogeneous zone (HZ) with altered conduction properties which may be part of the critical substrate for post-MI ventricular tachycardia. [2,3] Late gadolinium-enhanced (LGE) imaging is used for MI visualization, clearly depicting infarct size and transmurality due to the excellent contrast achieved between scar and viable tissue. However, with LGE uncertainty can be introduced by contrast agent kinetics. [4] Furthermore, LGE can lack information on tissue heterogeneity beyond “gray” areas that result from partial volume averaging and are assumed to be representative of the HZ. Conversely, scar tissue also exhibits increased T2, as fibrosis, primarily composed of collagen, increases interstitial water per unit volume. [5] Hence, direct and quantitative measurement of T2 relaxation time may be a feasible alternative for delineating viable myocardium and fibrosis with the additional benefit of depicting tissue heterogeneity.
Hydrophobic acceleration of Diels-Alder reactions (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHydrophobic acceleration of Diels-Alder reactionsDarryl C. Rideout and Ronald BreslowCite this: J. Am. Chem. Soc. 1980, 102, 26, 7816–7817Publication Date (Print):December 1, 1980Publication History Published online1 May 2002Published inissue 1 December 1980https://pubs.acs.org/doi/10.1021/ja00546a048https://doi.org/10.1021/ja00546a048research-articleACS PublicationsRequest reuse permissionsArticle Views10094Altmetric-Citations1324LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
The Structure of a Mycobacterial Outer-Membrane Channel (2004)

Mycobacteria have low-permeability outer membranes that render them resistant to most antibiotics. Hydrophilic nutrients can enter by way of transmembrane-channel proteins called porins. An x-ray analysis of the main porin from Mycobacterium smegmatis, MspA, revealed a homooctameric goblet-like conformation with a single central channel. This is the first structure of a mycobacterial outer-membrane protein. No structure-related protein was found in the Protein Data Bank. MspA contains two consecutive beta barrels with nonpolar outer surfaces that form a ribbon around the porin, which is too narrow to fit the thickness of the mycobacterial outer membrane in contemporary models.
Unique pharmacological property of ISRIB in inhibition of Aβ-induced neuronal cell death (2016)

A pharmacological approach to ameliorate Alzheimer's disease (AD) has not yet been established. In the present study, we investigated the pharmacological characteristics of the recently identified memory-enhancing compound, ISRIB for the amelioration of AD. ISRIB potently attenuated amyloid β-induced neuronal cell death at concentrations of 12.5-25 nM, but did not inhibit amyloid β production in the HEK293T cell line expressing the amyloid precursor protein (APP). These results suggest that ISRIB possesses the unique pharmacological property of attenuating amyloid β-induced neuronal cell death without affecting amyloid β production.
An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models (2008)

The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-kappaB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.
Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression (2003)

After brief periods of heightened stimulation, calcium entry through L-type calcium channels leads to activation of the transcription factor cAMP response element-binding protein (CREB) and CRE-dependent transcription. Many of the details surrounding the mechanism by which L-type calcium channels are privileged in signaling to CREB, to the exclusion of other calcium entry pathways, has remained unclear. We hypothesized that the PDZ interaction sequence contained within the last four amino acids of the calcium channel alpha1C (Ca(V)1.2) subunit [Val-Ser-Asn-Leu (VSNL)] is critical for L-type calcium channels (LTCs) to interact with the signaling machinery that triggers activity-dependent gene expression. To disrupt this interaction, hippocampal CA3-CA1 pyramidal neurons were transfected with DNA encoding for enhanced green fluorescent protein tethered to VSNL (EGFP-VSNL). EGFP-VSNL significantly attenuated L-type calcium channel-induced CREB phosphorylation and CRE-dependent transcription, although somatic calcium concentrations after stimulation remained unchanged. The effect of EGFP-VSNL was specific to the actions of L-type calcium channels, because CREB signaling after NMDA receptor stimulation remained intact. The importance of the PDZ interaction sequence was verified using dihydropyridine (DHP)-insensitive alpha1C subunits. Neurons transfected with alpha1C lacking the terminal five amino acids (DHP-LTCnoPDZ) exhibited attenuated CREB responses in comparison with cells expressing the full-length subunit (DHP-LTC). Collectively, these data suggest that localized calcium responses, regulated by interactions with PDZ domain proteins, are necessary for L-type calcium channels to effectively activate CREB and CRE-mediated gene expression.
TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer (2018)

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.
INTRAVENOUSLY ADMINISTERED SACCHARATED IRON OXIDE IN THE TREATMENT OF HYPOCHROMIC ANEMIA (1950)

Saccharated iron oxide given intravenously has recently been used successfully by several groups of British investigators for the treatment of iron deficiency anemia.<sup>1</sup>The therapeutic response has been uniformly good; reactions have been both infrequent and mild. It is surprising that the preparation can be injected with relative safety since all other forms of iron administered parenterally have caused reactions so severe that their use had to be abandoned; these include ferrous citrate, iron citrate green, ferrous gluconate, ferrous ascorbate, colloidal ferric hydroxide and colloidal ferric oxide.<sup>2</sup>The toxic manifestations commonly observed with the last two compounds were nausea, vomiting, abdominal and lower back pain, lacrimation, nasal stuffiness, headache, flushing and swelling of the face, swelling and stiffness of the tongue, paresthesias, fever, rapid fall in systolic blood pressure, substernal pain and a sense of impending death. The earlier studies with these therapeutically unsatisfactory iron preparations, however, had
Pyrroloisoquinoline antidepressants. 3. A focus on serotonin (1990)

A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.