gebhart/patrepeval huggingface dataset:
Abstract 5953: Regulation of androgen receptor stability by nuclear export protein CRM1 (2020)

Abstract Import of ligand-bound androgen receptor (AR) into the nucleus occurs with the help of nuclear importin. Past studies have identified a nuclear export signal (NES) in AR. CRM1 (also called XPO1 or Exportin1) is a well-studied exportin that exports proteins and RNA from the nucleus to the cytoplasm. GTP-bound active Ran, CRM1, and the cargo protein form a ternary complex that is exported through the nuclear pore complex. Previous experimental data indicate that RanGTP plays a vital role in Prostate cancer (PCa) progression. Our analyses further suggest that patients who have overexpression of CRM1 and/or Ran have significantly decreased survival. These results indicate that nucleocytoplasmic transport is essential for prostate cancer progression and inhibiting CRM1 could selectively inhibit cancer cell growth. We demonstrate that CRM1 does not affect the nuclear export of AR protein. However, quite surprisingly, we provide novel evidence that CRM1 binds to AR mRNA and is also required for AR protein stability. Inhibiting CRM1 using CRM1 inhibitor results in a dose-dependent rapid loss of AR and AR-V7 splice variants in PCa cells. This observation opens up an entirely new avenue to therapeutically regulate AR signaling using CRM1 inhibitors. Citation Format: Naiju Thomas, Rajendra Kumar, Deven Topiwala, Kavya Boyapati, Suthicha Kanacharoen, Michael Carducci, Samuel Denmeade, Sushant K. Kachhap. Regulation of androgen receptor stability by nuclear export protein CRM1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5953.
Pathogen genomics: impact on human health. (2002)

Genome sequencing and analysis have yielded a rich harvest of fundamental information about pathogenesis and have raised significant new possibilities for effective therapeutic intervention. In Pathogen Genomics: Impact on Human Health, a panel of leading infectious disease researchers and pharmaceutical scientists comprehensively review the latest genomic technologies and their application to infectious disease prevention, diagnosis, and treatment. The authors' cross-disciplinary approach-with expertise acquired from studying disease-causing viruses, bacteria, fungi, and protozoa-reveals how sequence information from diverse pathogens has uncovered novel targets for drug discovery, antigenic determinants for vaccine development, as well as diagnostic tools. The authors also discuss the application of DNA microarrays and the impact of genome sequencing comparisons to the discovery and choices of novel drug targets. The result is a better understanding of how these tools can be used to explore the fundamentals of microbial pathogenesis, as well as how pathogens interact with each other and with their host environments. Broad-ranging and illuminating, Pathogen Genomics: Impact on Human Health offers today's infectious disease specialists an authoritative analysis of the new genomic technologies and their productive application to drug discovery, vaccine development, and diagnostics
Cross-reactive CD4 + T cells enhance SARS-CoV-2 immune responses upon infection and vaccination (2021)

The functional relevance of preexisting cross-immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)–reactive and SARS-CoV-2–cross-reactive CD4<sup>+</sup> T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that preexisting spike- and S816-830–reactive T cells were recruited into immune responses to SARS-CoV-2 infection and their frequency correlated with anti–SARS-CoV-2-S1-IgG antibodies. Spike–cross-reactive T cells were also activated after primary BNT162b2 COVID-19 messenger RNA vaccination and displayed kinetics similar to those of secondary immune responses. Our results highlight the functional contribution of preexisting spike–cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity after primary SARS-CoV-2 immunization and the high rate of asymptomatic or mild COVID-19 disease courses.
Ultraviolet Resonance Raman Examination of the Light-Induced Protein Structural Changes in Rhodopsin Activation (1997)

Ultraviolet resonance Raman (UVRR) spectra of rhodopsin and its metarhodopsin I and metarhodopsin II photointermediates have been obtained to examine the molecular mechanism of G-protein-coupled receptor activation. Spectra were acquired using a single-pass capillary flow technique in combination with a Littrow prism UV prefilter detection system. The UVRR difference spectra between rhodopsin and mearhodopsin I exhibit small differences assignalbe to tyrosine residues and no differences due to tryptophan. The UVRR difference spectra between rhodopsin and metarhodopsin II exhibit significant differences for vibrations of both tryptophan and tyrosine residues. Most importantly, there is and intensity decrease of the totally symmetric tryptophan modes at 759, 1008, and 1545 cm-1, an intensity decrease of the tryptophan W7 band at 1357 cm-1, and a frequency shift of the tryptophan W17 ban from 885 to 892 cm-1. These difference features are assigned to one or more tryptophan residues that reside in a hydrophobic, weakly hydrogen-bonding environment in rhodopsin and that are transferred to a less hydrophobic, non-hydrogen-bonding environment during rhodopsin activation. The available evidence suggests that Trp265 makes a dominant contribution to the tryptophan features in this difference spectrum. These results are interpreted with a model for rhodopsin activation in which retinal isomerization alters the interaction of Trp265 with the ionone ring of the retinal chromophore.
Laboratory Project in Wireless FSK Receiver Design (2004)

This paper describes a wireless local area network laboratory project that provides senior and first-year graduate students in microwave engineering courses the opportunity to design, build, and test several passive microstrip components and integrate them into a working system. Students design filters, couplers, amplifiers, diode detectors, quarter-wave transformers, antennas, and stub matching networks in weekly labs that parallel-lectures in a one-semester microwave engineering course. This paper also describes simple inexpensive prototyping and testing methods that have been used in this course. Laboratory materials and technical details of the design are provided on the web for students and educators.
Efficient Asymmetric Synthesis of P-Chiral Phosphine Oxides via Properly Designed and Activated Benzoxazaphosphinine-2-oxide Agents (2013)

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.
Trisubstituted Acridines as G-quadruplex Telomere Targeting Agents. Effects of Extensions of the 3,6- and 9-Side Chains on Quadruplex Binding, Telomerase Activity, and Cell Proliferation (2005)

The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-, 6-, and 9-positions. A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis. Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding, together with a telomerase inhibition assay. These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity. Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes. Long-term exposure of MCF7 cancer cells to a subset of the most active compounds, at doses lower than the IC(50) values, showed that one compound produced a marked decrease in population growth, accompanied by senescence, which is consistent with telomere targeting by this agent.
Double Diffraction of Phase Gratings in the Fresnel Region (1975)

Double diffraction of phase gratings in the Fresnel region is studied following the previous paper in which double diffraction of amplitude gratings was reported. For sinusodially modulated gratings, series expansion analysis of the contrast in the periodic change in transmitted light intensity as a function of relative displacement was made and the contrast is shown to reach nearly unity for appropriate amplitude of phase modulation. Experimental results on photoresist gratings are found to coincide qualitatively well with theoretical predictions. For double diffraction of two ultrasonic light modulators the characteristics are shown to depend not only on the modulation depth of ultrasonic wave but also on the widths of ultrasonic columns and the angle of incidence.
Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis (2016)

Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment.
A Block-Based LMS Using the Walsh Transform for Digital Predistortion of Power Amplifiers (2023)

A novel non-linear adaptive filter for the linearization of Radio Frequency (RF) Power Amplifiers (PAs) is presented. In this study, we aim at reducing the Digital Predistortion (DPD) complexity and enhancing its convergence speed for reduced computation time. The Walsh Transform is used as a computational basis for evaluating a predistorter (PD) model. The mathematical properties of the Walsh theory are exploited to adapt a memory polynomial (MP) in the sequency domain. A block-based Walsh LMS is introduced to seek the optimal PD coefficients. Simulations and results of linearization of class-AB PAs are exhibited. The comparison with conventional DPD algorithms shows that the proposed method converges 10 times faster with a reduction of 12% of the complexity for similar accuracy. Finally, a complete DPD architecture based on the Walsh Transform is proposed.
Reply: Is Warfarin the Right Anticoagulant in Idiopathic Pulmonary Fibrosis? (2012)

From the Authors:

We thank Drs. Bendstrup and Hilberg for their comments regarding the IPFnet ACE trial examining the use of warfarin in idiopathic pulmonary fibrosis (IPF), and agree with their premise for the need for further investigation of anticoagulant therapy in IPF (1).

We agree that the ACE study addresses the use of only warfarin in IPF. Importantly, there are several differences between ACE and the previous study examining the utility of anticoagulation in IPF by Kubo and coworkers (2). In the prior study, much less physiologically impaired patients with IPF were enrolled at hospitalization and placed on warfarin and prednisolone in combination, as opposed to warfarin alone. In fact, the number of subjects on both agents in ACE was very small. Furthermore, dalteparin, a low-molecular-weight heparin, was added during subsequent hospitalizations for acute exacerbation events. By allowing sicker patients in ACE, we both enhanced event rates, which was the objective, but may not have allowed sufficient time for a treatment effect to occur in altering the course of fibrosis.

There is a plethora of evidence demonstrating antifibrotic effects of anticoagulants, both dependent and independent of their anticoagulant actions (3). Factor VII activity has been demonstrated to be elevated in patients with interstitial lung disease, and specifically in IPF (3). Also recently demonstrated, factor VIIa stimulates proliferation of human lung fibroblasts and extracellular matrix in a PAR-2–dependent manner. This effect is factor Xa and thrombin independent (4). Additionally shown after ACE’s inception is that increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury (5). Furthermore, evidence supports a protective role for protein C, a vitamin K–dependent anticoagulant protein, on the endothelial cell barrier function in acute lung injury (6). This growing body of evidence supports the concept that anticoagulants targeting specific coagulation factors or their “fibrosis-signaling” receptors may exert antifibrotic effects independent of their anticoagulant activities.

Heparin shares anticoagulant action with warfarin, but its coagulation factor targets only partially overlap with that of warfarin. Furthermore, different heparin size fractions, and biochemical modifications, differ in their potencies, anticoagulant targets (such as thrombin or Factor X), and in their antiinflammatory and antiproliferative capacities (7–9). There is much evidence in vitro and in vivo to suggest that all anticoagulants are not equal with respect to their antifibrotic therapeutic potential. Thus, we agree that the compelling basic science and animal model observations would provide a solid foundation upon which to implement additional trials of “anti-coagulants” in IPF. In conclusion, we have answered the question of the utility of warfarin in progressive IPF, but many questions remain.
Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis (2020)

Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.
Anti-inflammatory Efficacy of Combined Natural Alkaloid Berberine and S1PR Modulator Fingolimod at Low Doses in Ulcerative Colitis Preclinical Models (2020)

The natural alkaloid berberine is being studied as a drug candidate for the treatment of ulcerative colitis (UC). Fingolimod is an immunomodulator approved for the treatment of multiple sclerosis. Whether fingolimod use can be extended to UC and how it interacts with berberine remain unclear. In the present study, the anti-inflammatory efficacies of berberine, fingolimod, and a combination of half-doses of them was examined in mice with dextran sulfate sodium-induced colitis. In mice with subchronic colitis, 14-day oral administration of fingolimod had greater efficacy than berberine in ameliorating the disease clinical severity and colon shortening. However, in mice with chronic colitis, 30-day oral administration of berberine was more effective than fingolimod except on splenic swelling. Notably, the combination of half-doses of each drug was equally effective as the superior single drugs for two models and resulted in reduced splenic swelling in the chronic colitis model. The inhibition of cytokine expression and STAT3 activation, as well as binding to the sphingosine 1-phosphate receptor by both drugs, contributed to the combination efficacy. Our findings suggest that fingolimod in combination with berberine at reduced doses represents a novel therapy for UC that attains satisfactory efficacy with reduced potentials for adverse effects.
Natural antibodies to HIV‐tat epitopes and expression of HIV‐1 genes in vivo (1988)

The tat regulatory protein of HIV-1 was expressed as a fusion protein in E. coli and used as antigen to detect antibodies against HIV-tat (anti-tat) in the serum of HIV-1 infected children and adults. HIV-1-infected children showed a higher frequency (55%) of anti-tat than HIV-1-infected adults (36%). Anti-tat were present in only 15% (3/20) of acutely infected individuals. Forty percent (10/25) of individuals with prolonged HIV-1 infection but without antigen were anti-tat positive. Only 13% (3/23) of HIV-1-antibody-positive individuals with prolonged HIV-1 antigenemia were anti-tat positive and titers of anti-tat antibodies declined with time. Pepscan analysis identified the amino terminus of HIV-tat as the major antibody-binding site. Antibodies to HIV-tat occurred as a harbinger of HIV-1 antigen expression and disappeared thereafter, possibly reflecting the transience of HIV-tat expression. Because of the low antigenicity of HIV-tat, antibodies to this regulatory protein are not a reliable marker for either early HIV-1 infection or subsequent disease progression.
ChemInform Abstract: Diaryl Ester Prodrugs of FR900098 with Improved in vivo Antimalarial Activity. (2001)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform Abstract: Rapid Assembly of Polycyclic Structures via Sigmatropic Rearrangement of S‐Propargyl Xanthates. (2013)

Abstract Propargyl xanthates undergo rearrangement to afford intermediary bis(alkylidene)dithiolanones which are trapped by Diels‐Alder cycloaddition to yield dithiolones, representing three new carbocycle types such as (II), (VIII), and (X).
Affinity and Selectivity of β-Adrenoceptor Antagonists In Vitro (1985)

The potency order of the catecholamines (-)-isoprenaline (Iso), (-)-noradrenaline (NA), and (-)-adrenaline (Adr) in competition for radiolabelled sites is used for their pharmacological classification. It is shown that the radioligand 3H-CGP 12177 exclusively labels beta 1-adrenoceptors in rat salivary gland membranes (Iso greater than NA greater than Adr), and beta 2-adrenoceptors in rat reticulocytes (Iso greater than Adr greater than or equal to NA). These models are then used to derive the subtype-selectivity of the classical beta-adrenoceptor antagonists (+/-)-propranolol (prop; twofold beta 2-selective) and (+/-)-atenolol (aten; 35-fold beta 1-selective), as well as of the newer antagonists (+/-)-betaxolol and (+/-)-bisoprolol (betax and biso; 35-fold and 75-fold beta 1-selective, respectively). The ligand with the highest selectivity is ICI 118,551 (ICI), with a 300-fold beta 2-subtype selectivity. For comparison with antagonistic effects in humans at given plasma concentrations, the equilibrium dissociation constants of the ligands are measured in the presence of native human plasma and yield values for the relative selectively labelled subtype in the mean (Ki-values in nmol/l): prop: 20, aten: 250, biso: 24, betax: 23, and ICI: 2.5.
Unambiguous Sequence Characterization of a Monoclonal Antibody in a Single Analysis Using a Nonspecific Immobilized Enzyme Reactor (2019)

Accurate sequence characterization is essential for the development of therapeutic antibodies by the pharmaceutical industry. Presented here is a methodology to obtain comprehensive sequence analysis of a monoclonal antibody. An enzyme reactor of immobilized Aspergillopepsin I, a highly stable nonspecific protease, was used to cleave reduced antibody subunits into a peptide profile ranging from 1 to 20 kDa. Utilizing the Thermo Orbitrap Fusion's unique instrument architecture combined with state-of-the-art instrument control software allowed for dynamic instrument methods that optimally characterize eluting peptides based on their size and charge density. Using a data-dependent instrument method, both collisional dissociation and electron transfer dissociation were used to fragment the appropriate charge state of analyte peptides. The instrument layout also allowed for scans to be taken in parallel using both the ion trap and Orbitrap concurrently, thus allowing larger peptides to be analyzed in high resolution using the Orbitrap while simultaneously analyzing tryptic-like peptides using the ion trap. We harnessed these capabilities to develop a custom method to optimally fragment the eluting peptides based on their mass and charge density. Using this approach, we obtained 100% sequence coverage of the total antibody in a single chromatographic analysis, enabling unambiguous sequence assignment of all residues.
17O chemical shifts and deuterium isotope effects on13C chemical shifts of intramolecularly hydrogen-bonded compounds (1998)

17O chemical shifts were measured in 40 enamines activated in the β-position by C=O, COO, NO2, SO and SO2 groups. Data for the oxygen-containing series of o-hydroxyacyl aromatics are also included for comparison. Intramolecular hydrogen bonding in the enamines is discussed in terms of the acceptor and donor groups and the separating link. 17O chemical shifts, the two-bond deuterium isotope shifts on C-α 13C shifts and 1H NH or OH chemical shifts are correlated to show the interrelations of these parameters in elucidating intramolecular hydrogen bonds and their strength in a wide variety of compounds. 17O chemical shifts in open-chain compounds are shown to reflect intramolecular hydrogen bonding by a change to lower frequency whereas for five-membered rings steric effects cause higher frequency chemical shifts. © 1998 John Wiley & Sons, Ltd.