gebhart/patrepeval huggingface dataset:
Decompositions of multiply charged oligonucleotide anions (1993)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDecompositions of multiply charged oligonucleotide anionsScott A. McLuckey and Sohrab Habibi-GoudarziCite this: J. Am. Chem. Soc. 1993, 115, 25, 12085–12095Publication Date (Print):December 1, 1993Publication History Published online1 May 2002Published inissue 1 December 1993https://pubs.acs.org/doi/10.1021/ja00078a054https://doi.org/10.1021/ja00078a054research-articleACS PublicationsRequest reuse permissionsArticle Views690Altmetric-Citations257LEARN 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
Small Molecule Modulators of Toll-like Receptors (2008)

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTSmall Molecule Modulators of Toll-like ReceptorsMichael Czarniecki†View Author Information Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Mailstop 3655, Kenilworth, New Jersey 07033, USA† Contact information. Phone: +1 908 740 3480. Fax: +1 908 740 7152. E-mail: [email protected]Cite this: J. Med. Chem. 2008, 51, 21, 6621–6626Publication Date (Web):October 2, 2008Publication History Received29 July 2008Published online2 October 2008Published inissue 13 November 2008https://pubs.acs.org/doi/10.1021/jm800957khttps://doi.org/10.1021/jm800957kreview-articleACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views3338Altmetric-Citations44LEARN 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 SUBJECTS:Agonists,Immunology,Peptides and proteins,Receptors,Structure activity relationship Get e-Alerts
Simulating patients with Parallel Health State Networks. (1998)

The American Board of Family Practice is developing a computer-based recertification process to generate patient simulations from a knowledge base. Simulated patients require a stochastically generated history and response to treatment, suggesting a Monte Carlo-like patient generation process. Knowledge acquisition experiments revealed that description of a patient's overall health as a node in a Monte Carlo model was difficult for domain experts to use, severely limited knowledge reusability, and created a plethora of awkwardly defined health states. We explored a model in which patients traverse several parallel health state networks simultaneously, so that overall health is a vector describing the current nodes from every Parallel Network. This model has a reasonable biological basis, more easily defined data, and greatly improved reuse potential, at the cost of more complex simulation algorithms. Experiments using osteoarthritis stages, weight classification, and absence or presence of gastric ulcers as three Parallel Networks demonstrate the feasibility of this approach to simulating patients.
Photomixing at 1.55 µm in ion-irradiated In(0.53)Ga(0.47)As on InP (2006)

We report the first demonstration of a terahertz photomixer made of ion-irradiated In(0.53)Ga(0.47)As lattice-matched to InP and fiber-optic coupled with the drive lasers. A continuous-wave radiation is generated at frequencies up to 0.8 THz by photomixing two continuous-wave laser diodes around 1.55 microm. The measured 3dB-down bandwidth of 300 GHz yields a carrier lifetime of 0.53 ps, in agreement with the value of 0.41 ps measured in pump probe experiments. The detected signal is at the most 15 dB lower than the one obtained from similar photomixers fabricated from low-temperature-grown GaAs.
In vitro Inhibition and Stimulation of Purified Prostaglandin Endoperoxide Synthase by Flavonoids: Structure-Activity Relationship (1992)

We studied the effects of 37 flavonoids on prostaglandin endoperoxide synthase (EC 1.14.99.1) purified from sheep vesicular glands. Nonplanar flavans were more potent inhibitors than planar flavones and flavonols (IC50 values were, e.g., 40 mumol/l for catechin and epicatechin, 110 mumol/l for galangin, 490 mumol/l for quercetin and 450 mumol/l for kaempherol). Different inhibition mechanisms were observed, i.e. uncompetitive inhibition for nonplanar flavonoids and competitive or noncompetitive inhibition for planar flavonoids. Potent inhibitors in the group of flavones were substances with an o-dihydroxy structure in the B ring and in the group of flavonol substances with two hydroxyl groups in position 5 and 7 of the A ring. None of the flavanones studied caused significant inhibition, except for the flavanone-3-ol, silibinin (silybin), which caused potent inhibition with an IC50 of 120 mumol/l. Several flavonoids, which were able to inhibit the prostaglandin endoperoxide synthase at higher concentrations, were also able to stimulate the enzyme at lower concentrations. These results indicate that the flavonoids should be divided into two groups according to their capacity to inhibit the prostaglandin endoperoxide synthase, represented by planar and nonplanar substances as in each group a close correlation between structure and inhibitory activity was observed.
A Steady-state and Pre-steady-state Kinetic Analysis of the NTPase Activity Associated with the Hepatitis C Virus NS3 Helicase Domain (1996)

The helicase domain of hepatitis C virus NS3 (genotype 1b) was expressed in Escherichia coli and purified to homogeneity. The purified protein catalyzed the hydrolysis of nucleoside triphosphates (NTP) and the unwinding of duplex RNA in the presence of divalent metal ion. The enzyme was not selective for the NTP substrate. For example, UTP and acyclovir triphosphate were hydrolyzed efficiently by the enzyme. The rate of NTP hydrolysis was stimulated up to 27-fold by oligomeric nucleic acids (NA). Furthermore, NA bound to the enzyme with concomitant quenching of the intrinsic protein fluorescence. The dissociation constants of the enzyme for selected NA in the absence of NTP were between 10 and 35 microM at pH 7.0 and 25 degrees C. The enzyme had maximal affinity for NA with 12 or more nucleotides. A detailed steady-state and pre-steady-state kinetic analysis of ATP hydrolysis was made with (dU)18 as the effector. The kcat values for ATP hydrolysis in the presence and absence of (dU)18 were 80 s-1 and 2.7 s-1, respectively. The association (dissociation) rate constants for the enzyme and (dU)18 in the presence and absence of ATP were 5.7 microM-1 s-1 (3.9 s-1) and 290 microM-1 s-1 (2.27 s-1), respectively. The association (dissociation) rate constants for the enzyme and ATP in the presence and absence of (dU)18 were 0.4 microM-1 s-1 (<0.5 s-1) and 0.9 microM-1 s-1 (<10(-1) s-1), respectively. These data were consistent with a random kinetic mechanism.
TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors (2016)

Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1-mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8(+) T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways. Cancer Res; 76(8); 2087-93. ©2016 AACR.
Angiotensin II Increases Tissue Endothelin and Induces Vascular Hypertrophy (1997)

Our results therefore demonstrate that angiotensin II increases the production of endothelin in the blood vessel wall that, via ET(A) receptors, mediates changes in vascular structure of the cerebral and mesenteric circulation. Endothelin antagonists may therefore be of value to reduce blood pressure and to prevent vascular structural changes in conditions of increased activity of the renin-angiotensin system.
Infrared Signature of Structures Associated with the H + (H 2 O) n ( n = 6 to 27) Clusters (2004)

We report the OH stretching vibrational spectra of size-selected H+(H2O)n clusters through the region of the pronounced "magic number" at n = 21 in the cluster distribution. Sharp features are observed in the spectra and assigned to excitation of the dangling OH groups throughout the size range 6 </= n </= 27. A multiplet of such bands appears at small cluster sizes. This pattern simplifies to a doublet at n = 11, with the doublet persisting up to n = 20, but then collapsing to a single line in the n = 21 and n = 22 clusters and reemerging at n = 23. This spectral simplification provides direct evidence that, for the magic number cluster, all the dangling OH groups arise from water molecules in similar binding sites.
Typing of Multiple Single-Nucleotide Polymorphisms by a Microsphere-Based Rolling Circle Amplification Assay (2007)

The combination of suspension array with rolling circle amplification can lead to a sensitive and specific assay for single-nucleotide polymorphisms (SNPs) detection, as demonstrated in this study. A circular template generated by ligation upon the recognition of a point mutation on DNA targets was amplified isothermally by the Phi29 polymerase on microspheres. The elongation products were labeled with fluorochrome-tagged probes and detected in a flow cytometer, indicating the mutation occurrence. As low as 10 amol of mutated strands was detected by this assay, and positive mutation detection was achieved with a wild-type to mutant ratio of 10 000:1, which could be attributed to the high amplification efficiency of Phi29, the high binding capacity of the microspheres, and the remarkable precision of DNA ligase in distinguishing mismatched bases at the ligation site. A novel design of using two differently labeled detection probes on the same microsphere to target both the wild-type and mutant samples allowed parallel determination of the heterozygosity for two SNPs (K-ras G12C and TP53 R273H) in PCR amplicons prepared from human genomic DNA extracts. This ability lays the groundwork for further enhancing the assay throughput by using multiple fluorophores and microspheres with distinct properties.
Performance of large low-associativity caches (2010)

While it is known that lowering the associativity of caches degrades cache performance, little is understood about the degree of this effect or how to lessen the effect, especially in very large caches. Most existing works on cache performance are simulation or emulation based and there is a lack of analytical\ models characterizing performance in terms of different configuration parameters such as line size, cache size, associativity and workload specific parameters. We develop analytical models to study performance of large cache architectures by capturing the dependence of miss ratio on associativity and other configuration parameters. While high associativity may decrease cache misses, for very large caches the corresponding increase in hardware cost and power may be significant. We use our models as well as simulation to study different proposals for reducing misses in low associativity caches, specifically, address space randomization and victim caches. Our analysis provides specific detail on the impact of these proposals, and a clearer understanding of why they do or do not work.
2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus (2018)

A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).
Randomized Trial of Preventive Angioplasty in Myocardial Infarction (2013)

In patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses significantly reduced the risk of adverse cardiovascular events, as compared with PCI limited to the infarct artery. (Funded by Barts and the London Charity; PRAMI Current Controlled Trials number, ISRCTN73028481.).
Carbon monoxide, generated by heme oxygenase‐1, mediates the enhanced permeability and retention effect in solid tumors (2011)

The enhanced permeability and retention (EPR) effect is a unique pathophysiological phenomenon of solid tumors that sees biocompatible macromolecules (>40 kDa) accumulate selectively in the tumor. Various factors have been implicated in this effect. Herein, we report that heme oxygenase-1 (HO-1; also known as heat shock protein 32) significantly increases vascular permeability and thus macromolecular drug accumulation in tumors. Intradermal injection of recombinant HO-1 in mice, followed by i.v. administration of a macromolecular Evans blue-albumin complex, resulted in dose-dependent extravasation of Evans blue-albumin at the HO-1 injection site. Almost no extravasation was detected when inactivated HO-1 or a carbon monoxide (CO) scavenger was injected instead. Because HO-1 generates CO, these data imply that CO plays a key role in vascular leakage. This is supported by results obtained after intratumoral administration of a CO-releasing agent (tricarbonyldichlororuthenium(II) dimer) in the same experimental setting, specifically dose-dependent increases in vascular permeability plus augmented tumor blood flow. In addition, induction of HO-1 in tumors by the water-soluble macromolecular HO-1 inducer pegylated hemin significantly increased tumor blood flow and Evans blue-albumin accumulation in tumors. These findings suggest that HO-1 and/or CO are important mediators of the EPR effect. Thus, anticancer chemotherapy using macromolecular drugs may be improved by combination with an HO-1 inducer, such as pegylated hemin, via an enhanced EPR effect.
Tissue-Specific Homing and Expansion of Donor NK Cells in Allogeneic Bone Marrow Transplantation (2009)

NK cells have potential therapeutic impact in suppressing graft-versus-host disease (GVHD) and enhancing antitumor effects as a cellular therapy for hematologic malignancies. However, few studies have addressed the trafficking and in vivo behavior of NK cells in murine models of bone marrow transplantation (BMT). We investigated NK cell trafficking and survival following allogeneic and syngeneic BMT using a novel bioluminescence-based imaging strategy. Transplantation of luciferase-expressing NK cells revealed CD62L-mediated trafficking to lymphoid organs and trafficking to GVHD target tissues, as evidenced by in vivo and ex vivo bioluminescence imaging. The NK cells persisted for approximately 4 wk after transplantation in allogeneic recipients, but were not detectable in syngeneic recipients. CFSE-labeling studies showed extensive NK cell proliferation in vivo. Transplanted NK cells up-regulated molecules necessary for homing to the lymph nodes, gastrointestinal tract, and skin, yet did not cause clinical GVHD. This expansion and tissue-specific homing was not solely due to the conditioning regimen, as NK cells proliferated and reached lymphoid and GVHD target tissue in unconditioned allogeneic RAG2(-/-) gamma-chain(-/-) recipients. IL-2 enhanced expansion and antitumor activity of NK cells. These results provide significant insight into the behavior and potential therapeutic impact of NK cells in BMT.
24.2 A 0.1-to-3.1GHz 4-element MIMO receiver array supporting analog/RF arbitrary spatial filtering (2017)

Digital receiver (RX) arrays featuring ADCs at each element enable massive multi-in-multi-out (MIMO) applications, but since spatial interference rejection is absent in the RF/analog domain, RF/analog/ADC dynamic range is challenged in an environment where strong and weak spatially distinct in-band signals co-exist. Recent MIMO RX array works [1,2] attempt to mitigate this problem with (single) spatial notch suppression in the RF/analog domain, while still maintaining multiple outputs to support MIMO. However, multiple spatial interference signals at different power levels can be present, and reflections and scattering can make the power distribution in the spatial domain more hostile. A single spatial notch is insufficient in such realistic scenarios. Secondly, the notch suppression bandwidth (BW) is typically limited, as is the case with conventional cancellation architectures. Thirdly, reconfigurable wideband MIMO RX arrays that rely on impedance translation concepts in RF switched-capacitor circuits seldom operate effectively beyond 2GHz in CMOS [1].
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease (2010)

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.
Ophthalmic Medications (1948)

Journal Article Ophthalmic Medications Get access Milton W. Skolaut Milton W. Skolaut Search for other works by this author on: Oxford Academic Google Scholar The Bulletin of the American Society of Hospital Pharmacists, Volume 5, Issue 4, 1 August 1948, Pages 172–179, https://doi.org/10.1093/ajhp/5.4.172 Published: 01 August 1948
Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow (1992)

Abstract Using multidimensional flow cytometry we have defined and quantified the human T-cell differentiation pathway, focusing on those events occurring among the most immature thymocytes and putative bone marrow (BM) T-precursors. Early thymocytes were found to express the CD34 antigen and consisted of a mean 1.2% of cells within human pediatric (n = 9) and 2.0% in fetal thymi (n = 4). All CD34+ thymocytes were atypical blast by morphology, expressed intracytoplasmatic, but not cell surface, CD3, and were cell surface CD2+, CD5+, CD7+, CD38+, CD45+, CD45RA+, CD49d+, and LECAM-1(Leu8)high. CD34high thymocytes lacked surface expression of CD4 and CD8, but as CD34 expression diminished there was a coordinate increase in CD4 levels, followed by the appearance of CD8. The expression of CD1 and CD10 also increased concomitant with the loss of CD34, whereas expression of LECAM-1 diminished with CD34 downregulation. The differential expression of these antigens on early thymocytes (as well as the number of thymocytes displaying these patterns) was highly reproducible among the nine pediatric and four fetal specimens examined, suggesting a precise, stereotyped regulation of early differentiation events. Cell populations with antigen expression patterns suggestive of pluripotent stem cell (CD34high, CD38-), or non-T-lineage committed stem cells (CD34+, CD33+ or CD34+, CD19+) were not identified in either fetal or pediatric thymi (sensitivity = 1/10(4)). The presence of cells with the antigenic profile of the earliest CD34+ thymocytes was explored in human BM. Putative BM T-cell precursors with the appropriate phenotype (CD34+, CD7+, CD5+, CD2+, LECAM-1high) were readily identified in fetal specimens (constituting +/- 2% of the CD34+ population), but could not be reliably detected in adults. In contrast with thymi, only 13% of these cells expressed cytoplasmatic CD3, suggesting the presence of the immediate precursor of the putative prothymocyte population. This was further supported by the detection of CD34bright, CD7+, CD2-, CD5-, LECAM-1moderate cells in fetal specimens. Our results document the flow of cell surface differentiation during T-lymphopoiesis and suggest that T-lineage features are first acquired in the BM. The ability to reproducibly identify and isolate T-cell precursor populations of precisely defined maturational stage in marrow and thymus by multiparameter flow cytometry will facilitate characterization of the molecular events controlling T-lineage differentiation.