gebhart/patrepeval huggingface dataset:
Discovery and SAR of a Novel Selective and Orally Bioavailable Nonpeptide Classical Competitive Inhibitor Class of Protein-Tyrosine Phosphatase 1B (2002)

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.
Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation (2019)

Type I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC have yet to be elucidated. Herein, we evaluated the anti-tumor mechanisms of IFN-I in UC in human patients and in mice. Patient tumors from a Phase I clinical trial with adenoviral interferon-α (Ad-IFNα/Syn3) showed increased expression of T cell and checkpoint markers following treatment with Ad-IFNα/Syn3 by RNAseq and immunohistochemistry analysis in 25% of patients. In mice, peritumoral injections of poly(I:C) into MB49 UC tumors was used to incite an IFN-driven inflammatory response that significantly inhibited tumor growth. IFN-I engaged both innate and adaptive cells, seen in increased intratumoral CD8 T cells, NK cells, and CD11b<sup>+</sup>Ly6G<sup>+</sup> cells, but tumor inhibition was not reliant on any one immune cell type. Nonetheless, poly(I:C)-mediated tumor regression and change in the myeloid cell landscape was dependent on IL-6. Mice were also treated with poly(I:C) in combination with anti-PD-1 monoclonal antibody (mAb) to assess for additional benefit to tumor growth and animal survival. When used in combination with anti-PD-1 mAb, IFN-I stimulation prolonged survival, coinciding with inhibition of angiogenesis and enriched gene signatures of metabolism, extracellular matrix organization, and MAPK/AKT signaling. Altogether, these findings suggest IFN-I's immune-driven antitumor response in UC is mediated by IL-6 and a collaboration of immune cells, and its use in combination with checkpoint blockade therapy can increase clinical benefit.
PUF ROKs (2010)

Cryptographers have proposed the notion of read-once keys (ROKs) as a beneficial tool for a number of applications, such as delegation of authority. The premise of ROKs is that the key is destroyed by the process of reading it, thus preventing subsequent accesses. While the idea and the applications are well-understood, the consensus among cryptographers is that ROKs cannot be produced by algorithmic processes alone. Rather, a trusted hardware mechanism is needed to support the destruction of the key.
European Population Substructure: Clustering of Northern and Southern Populations (2006)

Using a genome-wide single nucleotide polymorphism (SNP) panel, we observed population structure in a diverse group of Europeans and European Americans. Under a variety of conditions and tests, there is a consistent and reproducible distinction between "northern" and "southern" European population groups: most individual participants with southern European ancestry (Italian, Spanish, Portuguese, and Greek) have >85% membership in the "southern" population; and most northern, western, eastern, and central Europeans have >90% in the "northern" population group. Ashkenazi Jewish as well as Sephardic Jewish origin also showed >85% membership in the "southern" population, consistent with a later Mediterranean origin of these ethnic groups. Based on this work, we have developed a core set of informative SNP markers that can control for this partition in European population structure in a variety of clinical and genetic studies.
Damage mechanics model for brittle failure of transversely isotropic solids : finite element implementation (2007)

A new continuum damage model, the wing crack damage (WCD) model, was developed for the analysis of brittle failure of transversely isotropic solids. Special attention was paid to the analysis of axial splitting under compression and tensile cracking under tension.\n\nIn addition to the WCD model a three-dimensional version of the damage model proposed by Murakami and Kamiya was enhanced and implemented in ABAQUS/Standard FE software.\n\nThe proposed WCD model is based on the use of the damage vector. The vector represents both the normal direction of the surface of the plane crack and the size of the damaged area. Damaging induces anisotropy in an originally transversely isotropic material. The evolution equations for damage are motivated by the wing crack growth mechanism. The evolution is based on propagation of pre-existing damage.\n\nThe proposed model enables modelling of pre-existing cracks. The feature can be exploited in studying the effect of orientation and size distribution of pre-existing cracks on the failure of materials. The model was implemented in ABAQUS/Standard FE software as a user subroutine.\n\nThe unsymmetrical behaviour of cracked materials under tension and compression due to the opening and closure of cracks is taken into account in the proposed model. In the work it was shown that the widely used strain-based crack closure criteria cannot be reliably applied in a two- and three-dimensional stress state. To attain a deformation localisation zone of finite width, a damage rate-dependent damage surface was introduced.\n\nThe validity of the proposed model was verified by testing it against five basic structures composed of known natural materials (ice, marble and concrete). The numerical simulations revealed the capability of the model in modelling brittle failure modes of transversely isotropic materials.
Purification and characterization of CMP-N-acetylneuraminic acid hydroxylase from pig submandibular glands (1994)

N-Glycoloylneuraminic acid (Neu5Gc) is synthesized as its CMP-glycoside by the action of CMP-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase. This enzyme is a soluble cytochrome b5-dependent monooxygenase and has been purified to apparent homogeneity from pig submandibular glands by precipitation with N-cetyl-N,N,N-trimethylammonium bromide and fractionation on Q-Sepharose, Cibacron Blue 3GA-Agarose, Reactive Brown 10-Agarose, Hexyl-Agarose and Superose S.12. This procedure resulted in an 8960-fold purification of the hydroxylase with a recovery of 0.8%. The molecular mass of this protein was shown to be 65 kDa on SDS-PAGE and approximately 60 kDa as determined by gel filtration on Superose S.12, which suggests that the enzyme is a monomer. The purified CMP-Neu5Ac hydroxylase is activated by FeSO4 and inhibited by iron-binding reagents such as o-phenanthroline, KCN, Tiron and ferrozine. An apparent Km of 11 microM was determined for the substrate CMP-Neu5Ac using purified hydroxylase in the presence of Triton X-100-solubilized microsomes. In a reconstituted system consisting of purified hydroxylase, cytochrome b5, cytochrome b5 reductase and catalase, an apparent Km of 3 microM was measured. The apparent Km for cytochrome b5 in this system was 0.24 microM. Immunization of a rabbit with enriched and purified hydroxylase led to an antiserum that inhibited CMP-Neu5Ac hydroxylase activity and reacted with the purified 65 kDa protein on a Western blot after SDS-PAGE. Antibodies specific for this 65 kDa protein were isolated and showed a strong reaction with the purified CMP-Neu5Ac hydroxylase from mouse liver after immunoblotting.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of Low-Intensity Ultrasound on Chondrogenic Differentiation of Mesenchymal Stem Cells Embedded in Polyglycolic Acid: An in Vivo Study (2006)

In this study we investigated the effects of LIUS on chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSC). Our hypothesis is that LIUS may be a noninvasively effective stimulant to a biological system in vivo by turning on differentiation of MSCs and promotion of chondrogenesis. MSCs were isolated from the bone marrow of New Zealand white rabbits and cultured in monolayer for 2 weeks. They were then harvested and seeded into polyglycolic acid (PGA) non-woven mesh at a number of 5 x 10(6) cells. Cultured with a chondrogenic-defined media for 1 week, the PGA/MSCs constructs (n = 4) were implanted subcutaneously in the back of nude mice (n = 9, each group). The ultrasound (US) group received US stimulation at a frequency of 0.8 MHz and intensity of 200 mW/cm(2) for 10 min every day up to 4 weeks, while the control group had no US stimulation. Analyses of histological, immunohistochemical, biochemical, and mechanical characteristics were made at 1, 2, and 4 weeks post-stimulation, respectively. Total DNA contents showed no significant difference between the two groups. Total collagen and glycosaminoglycan (GAG) increased more significantly in the US-stimulated group than in the control. Histology of Safranin O/Fast green confirmed more intense and spreading extracellular matrix (ECM) at 2 and 4 weeks in the US-stimulated specimens. Mechanical tests exhibited that compressive strengths were also significantly higher in the US-stimulated cells at later times. This study strongly suggests that it may be possible for ultrasound to have some stimulatory effects in vivo on the chondrogenesis of MSCs.
Traceless Capping Agent for Peptide Sequencing by Partial Edman Degradation and Mass Spectrometry (2006)

An improved method for the rapid sequence determination of biologically active peptides selected from one-bead-one-peptide combinatorial libraries has been developed. In this method, beads carrying unique peptide sequences were subjected to multiple cycles of partial Edman degradation (PED) by the treatment with a 15-30:1 mixture of phenyl isothiocyanate and N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSU), to generate a series of sequence-specific truncation products (a peptide ladder) for each resin-bound peptide. Following PED, the Fmoc group was removed from the N-terminus and any reacted side chains by piperidine treatment. The sequence of the full-length peptide on each bead was then determined by matrix-assisted laser desorption ionization mass spectrometry. The use of Fmoc-OSU as a traceless capping agent resulted in cleaner MS spectra and improved reliability for sequence assignment. This rapid, sensitive, and inexpensive sequencing method should further expand the utility of combinatorial peptide libraries in biomedical research.
Sybil: Methods and Software for Multiple Genome Comparison and Visualization (2007)

With the successful completion of genome sequencing projects for a variety of model organisms, the selection of candidate organisms for future sequencing efforts has been guided increasingly by a desire to enable comparative genomics. This trend has both depended on and encouraged the development of software tools that can elucidate and capitalize on the similarities and differences between genomes. "Sybil," one such tool, is a primarily web-based software package whose primary goal is to facilitate the analysis and visualization of comparative genome data, with a particular emphasis on protein and gene cluster data. Herein, a two-phase protein clustering algorithm, used to generate protein clusters suitable for analysis through Sybil and a method for creating graphical displays of protein or gene clusters that span multiple genomes are described. When combined, these two relatively simple techniques provide the user of the Sybil software (The Institute for Genomic Research [TIGR] Bioinformatics Department) with a browsable graphical display of his or her "input" genomes, showing which genes are conserved based on the parameters supplied to the protein clustering algorithm. For any given protein cluster the graphical display consists of a local alignment of the genomes in which the clustered genes are located. The genomes are arranged in a vertical stack, as in a multiple alignment, and shaded areas are used to connect genes in the same cluster, thus displaying conservation at the protein level in the context of the underlying genomic sequences. The authors have found this display-and slight variants thereof-useful for a variety of annotation and comparison tasks, ranging from identifying "missed" gene models or single-exon discrepancies between orthologous genes, to finding large or small regions of conserved gene synteny, and investigating the properties of the breakpoints between such regions.
Highly Ordered Arrays of Mesoporous Silica Nanorods with Tunable Aspect Ratios from Block Copolymer Thin Films (2008)

Highly ordered arrays of mesoporous silica nanorods with a tunable aspect ratio can be fabricated using PEOm-b-PMA(Az)n block copolymer thin films as templates. Together, penetration of the films by the silica precursor and the film thickness control the SiO2 nanorod growth, and heights of almost 200 nm can be achieved. Inside the SiO2 nanorods, mesochannels with a diameter of ∼ 2 nm are formed that are aligned along the longitudinal axis of the rod. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2089/2008/c2010_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Critical contribution of IFN-gamma and NK cells, but not perforin-mediated cytotoxicity, to anti-metastatic effect of alpha-galactosylceramide. (2001)

The glycolipid alpha -galactosylceramide (alpha -GalCer), which is presented by CD1d and specifically activates Valpha 14 NKT cells, exerts a potent anti-metastatic effect when administered in vivo. In this study, we demonstrated that alpha -GalCer administration led to rapid elimination of NKT cells by apoptosis in the liver and spleen, after they produced IFN-gamma and IL-4. In contrast, a more prolonged secretion of IFN-gamma was observed by liver and splenic NK cells after alpha -GalCer administration. Cytotoxic activity of liver mononuclear cells was not augmented 3h after alpha -GalCer administration, but was increased at 24 h when NKT cells were mostly depleted. The alpha -GalCer-induced cytotoxic activity was abolished in IFN-gamma -deficient and NK cell-depleted mice as well as CD1-deficient mice, suggesting that the alpha -Galcer-induced cytotoxicity was mainly mediated by IFN-gamma -activated NK cells. While the alpha -GalCer-induced cytotoxicity in vitro was mostly perforin dependent, anti-metastatic effect of alpha -GalCer was impaired in NK cell-depleted or IFN-gamma -deficient mice but not in perforin-deficient mice. Collectively, these results indicated that the anti-metastatic effect of alpha -GalCer is mainly mediated by NK cells, which are activated secondarily by IFN-gamma produced by alpha -GalCer-activated NKT cells, in a perforin-independent manner.
Oral combination therapy for type 2 diabetes (2002)

For patients with type 2 diabetes, oral monotherapy may be initially effective for controlling blood glucose, but it is associated with a high secondary failure rate. (Primary failure is frequent only in patients with high baseline blood glucose at the time of beginning monotherapy, whereas secondary failure is to be expected in the course of the disease.) The different classes of oral agents used to treat type 2 diabetes have complementary mechanisms of action, and their use in combination often results in blood glucose reductions that are significantly greater than those that can be obtained with maximal doses of any single drug. A wide range of combinations (e.g. sulfonylurea plus metformin, a thiazolidinedione, or acarbose; metformin plus a thiazolidinedione or acarbose) have been used effectively to achieve glycemic control in patients in whom oral monotherapy has failed. The high secondary failure rates for oral monotherapy - and, moreover, the high primary failure rate in patients with very high blood glucose at diagnosis - coupled with the effectiveness of combination treatment, support the suggestion that multiple-drug regimens be considered for initial pharmacologic treatment in patients with symptomatic type 2 diabetes whose blood glucose is not controlled by diet alone.
A microfabricated electrical differential counter for the selective enumeration of CD4+ T lymphocytes (2011)

We have developed a microfabricated biochip that enumerates CD4+ T lymphocytes from leukocyte populations obtained from human blood samples using electrical impedance sensing and immunoaffinity chromatography. T cell counts are found by obtaining the difference between the number of leukocytes before and after depleting CD4+ T cells with immobilized antibodies in a capture chamber. This differential counting technique has been validated to analyze physiological concentrations of leukocytes with an accuracy of ∼9 cells per µL by passivating the capture chamber with bovine serum albumin. In addition, the counter provided T cell counts which correlated closely with an optical control (R(2) = 0.997) for CD4 cell concentrations ranging from approximately 100 to 700 cells per µL. We believe that this approach can be a promising method for bringing quantitative HIV/AIDS diagnostics to resource-poor regions in the world.
A frequency and timing period acquisition technique for OFDM systems (2002)

Symbol Pattern Abstract This paper introduces a frequency and timing period acquisition technique for orthogonal frequency division multiplexing (OFDM) systems. The proposed technique estimates both the frequency and timing pesiod offsets at the time by using only one pilot symbol with its suitable frequency assignment. Pseudo noise (PN) sequences are introduced to assign these frequencies of the pilot symbol so that the acquisition range can be widened. Numerical examples are given to show the estimate variances for both additive white Gaussian noise (AWGN) and multipath fading channels.
The sinoatrial node, a heterogeneous pacemaker structure (2000)

This article focuses on the regional heterogeneity of the mammalian sinoatrial (SA) node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (i(Na), i(Ca,L), i(to), i(K,r), i(K,s) and i(f)), expression of gap junction proteins (Cx40, Cx43 and Cx45), autonomic regulation, and ageing. Experimental studies on the single SA node cell to the whole animal are reviewed. The heterogeneity is considered in terms of the gradient model of the SA node, in which there is gradual change in the intrinsic properties of SA node cells from periphery to centre, and the alternative mosaic model, in which there is a variable mix of atrial and SA node cells from periphery to centre. The heterogeneity is important for the dependable functioning of the SA node as the pacemaker for the heart, because (i) via multiple mechanisms, it allows the SA node to drive the surrounding atrial muscle without being suppressed electrotonically; (ii) via an action potential duration gradient and a conduction block zone, it promotes antegrade propagation of excitation from the SA node to the right atrium and prevents reentry of excitation; and (iii) via pacemaker shift, it allows pacemaking to continue under diverse pathophysiological circumstances.
Baculovirus gp64 envelope glycoprotein is sufficient to mediate pH-dependent membrane fusion (1992)

The baculovirus gp64 envelope glycoprotein is a major component of the envelope of the budded virus (BV) and is involved in BV entry into the host cell by endocytosis. To determine whether gp64 alone was sufficient to mediate membrane fusion, the Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus gp64 protein was transiently expressed in uninfected insect cells. Cells expressing the baculovirus gp64 protein were examined for membrane fusion activity by using a syncytium formation assay under various conditions of exposure to low pH. Cells expressing the gp64 protein mediated membrane fusion and syncytium formation in a pH-dependent manner. A pH of 5.5 or lower was required to induce membrane fusion. In addition, exposure of gp64-expressing cells to low pH for as little as 5 s was sufficient to induce gp64-mediated syncytium formation. These studies provide direct evidence that gp64 is a pH-dependent membrane fusion protein and suggest that gp64 is the protein responsible for fusion of the virion envelope with the endosome membrane during BV entry into the host cell by endocytosis.
Further advances in electron-beam pattern generation technology for 180-nm masks (1998)

The technology in use in today's mask shop may not be adequate to meet 180 nm production requirements. In particular, requirements for linewidth control, linewidth uniformity, and registration are tightening at a breakneck pace. In the past, incremental improvements to registration and linewidth have been adequate to keep pace with steadily evolving mask requirements. This paradigm of continuous incremental improvement is not longer a valid model. Mask writers are needed that can deliver a higher dose to support advanced resists for superior critical dimension (CD) control, write faster to compensate for shrinking device sizes, and incorporate advanced calibration and error control schemes to improve placement accuracy. This paper describes key electron-beam pattern generation activities necessary to meet 180 nm mask requirements. This includes testing and implementation of multipass graybeam to improve throughput at lower addresses without compromising lithography quality, a new resist and process capable of supporting dry etching, and a data path capable of supporting addressing to 10 nm. Multipass gray (MPG) writing strategy was introduced with the MEBES 4500S. The ability to deliver a 4X improvement in dose while improving throughput is a significant advantage over previous MEBES systems. Because MPG is used in conjunction with offset scan voting, improvements in registration performance and a reduction in butting of over 50 percent have been demonstrated. Some of the process improvements attributed to a high dose mask writer are also documented in this paper. CD uniformity improvements with ZEP 7000 and dry etch at a 720 nm nominal feature size and smaller are also discussed in some detail.