gebhart/patrepeval huggingface dataset:
Alternative mechanisms with and without steel factor support primitive human hematopoiesis (1993)

As a first approach to defining the molecular requirements for supporting human hematopoietic stem cell maintenance and differentiation in vitro, we have analyzed and compared the ability of various factors to support the maintenance and initial differentiation of human long-term culture-initiating cells (LTC-ICs), a distinct, rare primitive hematopoietic cell type whose progeny after 5 weeks include cells detectable as colony-forming cells. Normal human marrow cells highly enriched in LTC-ICs (approximately 1% pure) were placed in cultures containing either preestablished, irradiated human marrow adherent feeder layers, or feeders consisting of Steel factor-deficient SI/SI, or normal +/+ murine fibroblasts, or no feeders. In some groups, either Steel factor alone, granulocyte colony-stimulating factor (G- CSF) and interleukin-3 (IL-3), or all three factors combined were also added repeatedly. SI/SI murine fibroblasts were equivalent to +/+ controls and to normal human marrow feeders in supporting both LTC-IC maintenance and clonogenic cell output over a 5-week period. Soluble Steel factor alone could, however, effectively substitute for human marrow feeders to support LTC-IC maintenance, although clonogenic cell output was markedly reduced under these conditions. Conversely, soluble Steel factor with G-CSF and IL-3 or with feeders (or all together) did not further enhance (or depress) LTC-IC maintenance, although under these conditions clonogenic cell output was markedly increased. These findings confirm previous evidence that LTC-IC maintenance and clonogenic cell production are differentially regulated and show for the first time that LTC-IC maintenance can be supported by different nonsynergizing factors that may, but need not, include Steel factor.
Antisense Inhibition and Adeno-Associated Viral Vector Delivery for Reducing Hypertension (1997)

Antisense oligodeoxynucleotides have been designed to inhibit the production of specific proteins. In models of hypertension, we have targeted the renin-angiotensin system at the level of synthesis (angiotensinogen) and the receptor (AT1 receptor). The design of antisense oligonucleotides requires choosing a site to inhibit mRNA processig or translation. The strategy we use is to make three oligonucleotides of antisense sequences, upstream and downstream from the AUG site and over the AUG site. The oligonucleotides are tested in a screening test. Antisense oligonucleotides to AT1-receptor mRNA and to angiotensinogen mRNA reduce blood pressure in spontaneously hypertensive rats when injected into the brain. They significantly reduce the concentration of the appropriate protein. The oligonucleotides are also effective when administered systemically. The decrease in blood pressure with antisense oligonucleotides delivered in blood or brain lasts 3 to 7 days. To prolong the action, direct injection of naked DNA and injection of DNA in liposome carriers have been tested. Viral vectors have been developed to deliver antisense DNA. The viral vectors available include retroviruses and adenovirus, but the adeno-associated virus (AAV) vector is the vector of choice for ultimate use in gene therapy. It offers safety because it is nonpathogenic, has longevity because it integrates into the genome, and has sufficient carrying capacity to carry up to 4.5 kb antisense or gene in a recombinant AAV. Using rAAV-antisense to AT1 mRNA, there is efficient transfection into cells and an inhibition of AT1 receptor number. In in vivo tests, rAAV-AS AT1-receptor when injected into the brains of SHR reduces blood pressure for more than 2 months. In young rats (3 weeks old), rAAV-AS AT1-receptor decreases blood pressure and slows the development of hypertension. While further experiments need to be done on dose-response relationships and on the cellular mechanisms of these effects, the results show the feasibility of AAV as a vector for antisense inhibition, which may ultimately be used in gene therapy for hypertension.
Intramolecular nitrogen-hydrogen, oxygen-hydrogen and sulfur-hydrogen insertion reactions. Synthesis of heterocycles from .alpha.-diazo .beta.-keto esters (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIntramolecular nitrogen-hydrogen, oxygen-hydrogen and sulfur-hydrogen insertion reactions. Synthesis of heterocycles from .alpha.-diazo .beta.-keto estersMikel P. Moyer, Paul L. Feldman, and Henry RapoportCite this: J. Org. Chem. 1985, 50, 25, 5223–5230Publication Date (Print):December 1, 1985Publication History Published online1 May 2002Published inissue 1 December 1985https://pubs.acs.org/doi/10.1021/jo00225a047https://doi.org/10.1021/jo00225a047research-articleACS PublicationsRequest reuse permissionsArticle Views3237Altmetric-Citations142LEARN 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
Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus (2014)

The prevalence of obesity and diabetes mellitus type 2 is increasing rapidly around the globe. Recent insights have generated an entirely new perspective that the intestinal microbiota may play a significant role in the development of these metabolic disorders. Alterations in the intestinal microbiota composition promote systemic inflammation that is a hallmark of obesity and subsequent insulin resistance. Thus, it is important to understand the reciprocal relationship between intestinal microbiota composition and metabolic health in order to eventually prevent disease progression. In this respect, faecal transplantation studies have implicated that butyrate-producing intestinal bacteria are crucial in this process and be considered as key players in regulating diverse signalling cascades associated with human glucose and lipid metabolism.
Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease (2000)

Our findings indicate that higher coffee and caffeine intake is associated with a significantly lower incidence of PD. This effect appears to be independent of smoking. The data suggest that the mechanism is related to caffeine intake and not to other nutrients contained in coffee. JAMA. 2000;283:2674-2679.
Effect of food or antacid on febuxostat pharmacokinetics and pharmacodynamics in healthy subjects (2005)

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Aim The effects of food and antacid on oral febuxostat pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated. Methods In 4 phase-1, two-period, crossover studies, male and female subjects received either a single dose (SD) of 40 mg (n=23) or 120 mg (n=19), or multiple dose (MD) 80 mg daily for 6 days (n=23) of febuxostat under non-fasting[test (T)] and fasting[reference (R)] conditions; or received a single 80 mg dose with (T) and without (R) an antacid (800 mg Mg(OH)2-900 mg Al(OH)3). Plasma febuxostat (LC-MS/MS method) and serum uric acid (sUA, PD marker, enzymatic assay) concentrations were assessed. Results A delay of tmax was observed with both food and antacid. Point estimates (PE) and confidence intervals (CI) for T and R ratios/differences are shown below for febuxostat Cmax, AUC and sUA 24-hour mean concentration (Cmean,24). (see Table) Even though food caused a decrease in the absorption rate and extent of febuxostat in all food effect studies, this decrease was not associated with a decrease in febuxostat PD effect (sUA), when evaluated in the 80 mg MD study. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Febuxostat was safe and well tolerated in all studies. Conclusion Febuxostat can be administered regardless of food or antacid intake. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: 10.1016/j.clpt.2004.12.083 Febuxostat Dose Febuxostat Cmax Febuxostat AUC1 Cmean,24 (%) Food Effect 40 mg SD 0.54 (0.48–0.61)2 0.81 (0.77–0.85)2 - 80 mg MD 0.51 (0.44–0.60)2 0.82 (0.78–0.87)2 6 (4–10) 120 mg SD 0.62 (0.52–0.74)2 0.84 (0.79–0.90)2 - Antacid Effect 80 mg SD 0.68 (0.58–0.79)2 0.85 (0.81–0.90)2 - 1 AUC∞[single dose (SD)] or AUC24[multiple dose (MD)] 2 T/R ratio PE (90% CI, log-transformed data) for febuxostat PK parameter ratios T-R difference PE (95% CI) for the % change from the baseline in Cmean,24
The C allele of the GNB3 C825T polymorphism of the G protein β3‐subunit is associated with an increased risk for the development of oncocytic thyroid tumours (2006)

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid-specific proteins and hormones, although they possess an intact thyroid-stimulating hormone receptor-adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender-matched healthy blood donors and a series of 327 non-oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non-oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C-allele frequency when compared with all non-oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure.
Nonfasting Triglycerides and Risk of Myocardial Infarction, Ischemic Heart Disease, and Death in Men and Women (2007)

In this general population cohort, elevated nonfasting triglyceride levels were associated with increased risk of MI, IHD, and death in men and women.
T- and B-Cell-Deficient Mice with Experimental Stroke have Reduced Lesion Size and Inflammation (2007)

Stroke induction in immunologically competent mice not only produces local ischemia and brain damage, but also induces early inflammatory changes in brain and peripheral immune responses. Although immune elements clearly are activated after brain vascular occlusion, the relative contribution of T and B lymphocytes to the developing lesion has not been quantified. We evaluated effects 22 h after middle cerebral artery occlusion (90 mins) on histologic injury and peripheral immune activation in severe combined immunodeficient (SCID) mice lacking T and B cells. Cortical and total infarct volumes were strikingly reduced in male SCID mice (n=14, 33+/-4% of contralateral cortex, n=10, 52+/-3% of contralateral hemisphere) versus immunologically intact C57BL/6 mice (wild type, n=9, 57+/-5% of contralateral cortex, 57+/-4% of contralateral hemisphere) (P<0.01). Striatal infarction was not altered (77+/-7% of contralateral striatum in SCID, 84+/-7% in wild type), suggesting that the core of the evolving ischemic lesion was not impacted by lack of T and B cells. As expected, inflammatory factors from immune cells in ischemic SCID brains were essentially absent, with the exception of interleukin-1beta increase in both SCID and wild type tissue. Spleen cell numbers were low in SCID mice, but were further reduced 22 h after stroke, with substantial reduction in most inflammatory factors except for increased expression of interferon-gamma and macrophage inflammatory protein (MIP)-2. These data quantify the damaging effect of T and B lymphocytes on early, evolving ischemic brain injury, and further implicate interleukin-1beta in brain and interferon-gamma and MIP-2 in spleen as inflammatory factors produced by cells other than T and B cells.
Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding (1995)

We have used a neuraminidase-deficient influenza virus, NWS-Mvi, which was selected by supplying bacterial neuraminidase in the medium (C. Liu and G. M. Air, Virology 194:403-407, 1993), to define the role of neuraminidase in influenza virus replication. Electron microscopy showed that virions of the NWS-Mvi mutant assembled normally and formed large aggregates associated with cell surfaces. The NWS-Mvi virus grown in the absence of neuraminidase was able to carry out a second round of replication in MDCK cells without added neuraminidase, indicating that the virus particles contained in these aggregates were infectious. Aggregates of virus were also found in cytoplasmic vacuoles. When virus-infected cells were incubated in the presence of ferritin, such aggregates were found to be labeled with ferritin, indicating that they are derived from uptake at the cell surface. When the neuraminidase-deficient virus was administered intranasally to C57BL/6 mice, low titers of virus were recovered from the lungs and major histocompatibility complex class I-restricted cytotoxic T cells were generated: evidence that cells were infected in vivo. In C57BL/6 nu/nu mice, the low level of virus persisted for at least 28 days but never increased. These results suggest that neuraminidase is not required for influenza virus entry, replication, or assembly in cell culture or in mice.
A model of plan inference that distinguishes between the beliefs of actors and observers (1986)

Existing models of plan inference (PI) in conversation have assumed that the agent whose plan is being inferred (the actor) and the agent drawing the inference (the observer) have identical beliefs about actions in the domain. I argue that this assumption often results in failure of both the PI process and the communicative process that PI is meant to support. In particular, it precludes the principled generation of appropriate responses to queries that arise from invalied plans. I describe a model of PI that abandons this assumption. It rests on an analysis of plans as mental phenomena. Judgements that a plan is invalid are associated with particular discrepancies between the beliefs that the observer ascribes to the actor when the former believes that the latter has some plan, and the beliefs that the observer herself holds. I show that the content of an appropriate response to a query is affected by the types of any such discrepancies of belief judged to be present in the plan inferred to underlie that query. The PI model described here has been implemented in SPIRIT, a small demonstration system that answers questions about the domain of computer mail.
Benzimidazole Derivatives as Kinase Inhibitors (2014)

Benzimidazole is a common kinase inhibitor scaffold and benzimidazole-based compounds interact with enzymes by multiple binding modes. In some cases, the benzimidazole acts as part of the hinge-binding motif, in others it has a scaffolding role without evidence for direct hinge binding. Several of these compounds are ATP-competitive inhibitors and show high selectivity by exploiting unique structural properties that distinguish one kinase from the majority of other kinases. However, the high specificity for a single target is not always sufficient. Thus another approach, called multi-target therapy, has been developed over the last few years. The simultaneous inhibition of various kinases may be useful because the disease is attacked at several relevant targets. Moreover, if a kinase becomes drug-resistant, a multitargeted drug can act on the other kinases. Some benzimidazole derivatives are multi-target inhibitors. In this article benzimidazole inhibitors are reported with their mechanisms of action, structure-activity relationship (SAR) and biological properties.
Studies related to antibody fragment (Fab) production in Escherichia coli W3110 fed‐batch fermentation processes using multiparameter flow cytometry (2008)

Microbiology is important to industry therefore rapid and statistically representative measurements of cell physiological state, proliferation, and viability are essential if informed decisions about fermentation bioprocess optimization or control are to be made, because process performance will depend largely on the number of metabolically active viable cells. Samples of recombinant Escherichia coli W3110, containing the gene for the D1.3 anti-lysozyme Fab fragment under the control of the lac-based expression system, were taken at various stages from fed-batch fermentation processes and stained with a mixture of bis-(1,3-dibutylbarbituric acid) trimethine oxonol and propidium iodide (PI/BOX). Where appropriate, measurements of dissolved oxygen tension (DOT), OD600nm and Fab concentration were made. Depending on time of induction the maximum amount of Fab accumulating in the supernatant varied quite markedly from 1 to 4 microg ml(-1) as did subsequent cell physiological state with respect to PI/BOX staining with a concomitant drop in maximum biomass concentration. Depending on point of induction a fourfold increase in Fab production could be achieved accompanied by a approximately 50% drop in maximum biomass concentration but with a higher proportion of viable cells as measured by multiparameter flow cytometry.
Properties of Ta2 O 5‐Based Dielectric Nanolaminates Deposited by Atomic Layer Epitaxy (1997)

Dielectric thin films and multilayers suitable for application as insulating layers in electroluminescent display devices have been studied. In this work, and nanolaminates with improved dielectric characteristics were grown by atomic layer epitaxy. The films were evaluated by capacitance and current‐voltage measurements, The pure , and films possessed charge‐storage factors up to 8, 16, and 19 nC/mm2, respectively, at a leakage current density of 1 μA/cm2. The nanolaminates were completely amorphous and their storage factors did not exceed 30 nC/mm2. The nanolaminates showed remarkably improved dielectric properties when compared with those of the pure oxide films, especially when the interlayer thicknesses were optimized. Nanosize crystallites of monoclinic and metastable tetragonal were observed in the nanolaminates by x‐ray diffraction. The nanolaminates possessed high charge‐storage factors up to 64 nC/mm2 and showed superior stability of the dielectric properties.
Monoclonal antibodies, antigens and molecular diagnostics: a practical overview. (1999)

The development of monoclonal antibody-based immunochemical assays to measure antibodies, antigens and small molecules, such as drugs, ushered in a revolution in modern diagnostic medicine. The impact of monoclonal antibodies on diagnostic imaging technologies and therapeutic regimes was equally dramatic. Additionally, the application of immunological techniques to the biochemical research lab was partially responsible for the exponential growth in our understanding of human physiology, biochemistry and genetics. Monoclonal antibody technology is limited, however, by the manner in which antigen-antibody interactions can be controlled and by the ability to consistently produce antibodies with appropriate affinity and specificity. Recent advances in recombinant antigen preparation and antibody engineering have been used to enhance the applications of this technology. In this review, current strategies to generate and engineer monoclonal antibodies as well as their clinical applications are summarized. A brief review of molecular diagnostics and its future trend is also included.
Computational Binding Studies of Orthogonal Cyclosporin‐Cyclophilin Pairs (1997)

A valuable tool for the design of ligands for bioreceptors is provided by the presented combination of Monte Carlo simulations and free energy perturbation calculations. Application of this methodology to an orthogonal receptor–ligand pair based on cyclosporin A and human cyclophilin reproduced the experimentally observed differences in binding affinities and gave detailed insights into the origin of binding preferences with the thermodynamic cycles given on the right. L: reference ligand; P: original protein; bL: bumped ligand; hP: holed protein.
Total Synthesis and Evaluation of [Ψ[CH2NH]Tpg4]Vancomycin Aglycon:  Reengineering Vancomycin for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding (2006)

An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.