gebhart/patrepeval huggingface dataset:
Mechanistic Analysis of a Type II Polyketide Synthase. Role of Conserved Residues in the β-Ketoacyl Synthase−Chain Length Factor Heterodimer (2000)

Type II polyketide synthases (PKSs) are a family of multienzyme systems that catalyze the biosynthesis of polyfunctional aromatic natural products such as actinorhodin, frenolicin, tetracenomycin, and doxorubicin. A central component in each of these systems is the beta-ketoacyl synthase-chain length factor (KS-CLF) heterodimer. In the presence of an acyl carrier protein (ACP) and a malonyl-CoA:ACP malonyl transferase (MAT), this enzyme synthesizes a polyketide chain of defined length from malonyl-CoA. We have investigated the role of the actinorhodin KS-CLF in priming, elongation, and termination of its octaketide product by subjecting the wild-type enzyme and selected mutants to assays that probe key steps in the overall catalytic cycle. Under conditions reflecting steady-state turnover of the PKS, a unique acyl-ACP intermediate is detected that carries a long, possibly full-length, acyl chain. This species cannot be synthesized by the C169S, H309A, K341A, and H346A mutants of the KS, all of which are blocked in early steps in the PKS catalytic cycle. These four residues are universally conserved in all known KSs. Malonyl-ACP alone is sufficient for kinetically and stoichiometrically efficient synthesis of polyketides by the wild-type KS-CLF, but not by heterodimers that carry the mutations listed above. Among these mutants, C169S is an efficient decarboxylase of malonyl-ACP, but the H309A, K341A, and H346A mutants are unable to catalyze decarboxylation. Transfer of label from [(14)C]malonyl-ACP to the nucleophile at position 169 in the KS can be detected for the wild-type enzyme and for the C169S and K341A mutants, but not for the H309A mutant and only very weakly for the H346A mutant. A model is proposed for decarboxylative priming and extension of a polyketide chain by the KS, where C169 and H346 form a catalytic dyad for acyl chain attachment, H309 positions the malonyl-ACP in the active site and supports carbanion formation by interacting with the thioester carbonyl, and K341 enhances the rate of malonyl-ACP decarboxylation via electrostatic interaction. Our data also suggest that the ACP and the KS dissociate after each C-C bond forming event, and that the newly extended acyl chain is transferred back from the ACP pantetheine to the KS cysteine before dissociation can occur. Chain termination is most likely the rate-limiting step in polyketide biosynthesis. Within the act CLF, neither the universally conserved S145 residue nor Q171, which aligns with the active site cysteine of the ketosynthase, is essential for PKS activity. The results described here provide a basis for a better understanding of the catalytic cycle of type II PKSs and fatty acid synthases.
Ireland (2013)

Ireland, comprising Northern Ireland and the Republic of Ireland, has a long and geologically diverse coastline in relation to the size of the island. The northern part of Ireland has been dominated by land uplift and sea levels have been static or falling for the past few thousand years. The southern part of Ireland, which was deglaciated much earlier, has experienced continuous rise in sea levels over the same period. The demographic and economic context is of some importance in understanding the impact of, and response to coastal erosion in Ireland. Coastal processes on the western coast of Ireland are driven by long-period swell waves that begin to interact with the seabed far from shore and consequently arrive at the coast fully refracted. Long-term erosion rates in eastern Ireland are variable both in time and space depending on past sediment supply and dispersal to a large extent.
Multiobjective Inverse Design of Solid-State Quantum Emitter Single-Photon Sources (2022)

Single solid-state quantum emitters offer considerable potential for the implementation of sources of single indistinguishable photons, which are central to many photonic quantum information systems. Nanophotonic geometry optimization with multiple performance metrics is imperative to convert a bare quantum emitter into a single-photon source that approaches the necessary levels of purity, indistinguishability, and brightness for quantum photonics. We present an inverse design methodology that simultaneously targets two important figures-of-merit for high-performance quantum light sources: the Purcell radiative rate enhancement and the coupling efficiency into a desired light collection channel. We explicitly address geometry-dependent power emission, a critical but often overlooked aspect of gradient-based optimization of quantum emitter single-photon sources. We illustrate the efficacy of our method through the design of a single-photon source based on a quantum emitter in a GaAs nanophotonic structure that provides a Purcell factor Fp = 21 with a 94% waveguide coupling efficiency, while respecting a geometric constraint to minimize emitter decoherence caused by etched sidewalls. Our results indicate that multiobjective inverse design can yield competitive performance with more favorable trade-offs than conventional approaches based on a pre-established waveguide or cavity geometries.
Combining 3D X-ray Techniques; Computed Tomography and Fluorescence (2018)

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Prevention of oxidative degradation of polyurethane by covalent attachment of di‐tert‐butylphenol residues (2006)

Polyurethane (PU) components of cardiovascular devices are subjected to oxidation-initiated surface degradation, which leads to cracking and ultimately device failure. In the present study, we investigated a novel bromoalkylation chemical strategy to covalently attach the antioxidant, di-tert-butylphenol (DBP), and/or cholesterol (Chol) to the PU urethane nitrogen groups to hypothetically prevent oxidative degradation. These experiments compared PU, PU-DBP, PU-Chol, and PU-Chol-DBP. A series of comparative oxidative degradation studies involved exposing PU samples (modified and unmodified) to H2O2-CoCl2 for 15 days at 37 degrees C, to cause accelerated oxidative degradation. The extent and effects of degradation were assessed by attenuated total reflectance Fourier transformation infrared spectroscopy (FTIR), scanning electron microscopy (SEM), surface contact angle measurements, and mechanical testing. Both the Chol and DBP modification conferred significant resistance to oxidation related changes compared to unmodified PU per FTIR and SEM results. SEM demonstrated cavitation only in unmodified PU. However, contact angle analysis showed significant oxidation-induced changes only in the Chol-modified PU formulations. Most importantly, uniaxial stress-strain testing revealed that only PU-DBP demonstrated bulk elastomeric properties that were minimally affected by oxidation; PU, PU-Chol, PU-Chol-DBP showed marked deterioration of their stress-strain properties following oxidation. In conclusion, these results demonstrate that derivatizing PU with DBP confers significant resistance to oxidative degradation compared with unmodified PU.
Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Nonanticoagulant Heparins (2008)

Abstract : Studies with mice bearing MCF7-WT xenografts demonstrate that encapsulation of Dox, whether in targeted or non-targeted PLGA nanoparticles, improved anti-tumor efficacy in comparison to un-encapsulated Dox. In animals bearing MCF7-R (Dox-resistant) tumors, administration of Dox encapsulated in alphavbeta-targeted nanoparticles or of Dox with nonanticoagulant heparin (NACH) are potent strategies for overcoming Dox resistance in animals bearing these aggressive human breast tumors. HPLC analyses of tumors and tissues from animals bearing MCF7-R tumors clearly demonstrate that LMWH or NACH increase the uptake of Dox into tumors but not other tissues at 3 and 24 hrs, at least double the amount observed with Dox alone. This is a highly significant result in the light of the fact that the FDA criterion for a clinically meaningful effect is a 15% increase in chemotherapeutic uptake. In vitro studies to investigate possible mechanisms associated with LMWH improvement of Dox anti-tumor activity focused on cell migration, proliferation and viability. LMWH compounds did not substantially affect these parameters in vitro. It is likely that increasing chemotherapeutic uptake in vivo as demonstrated in HPLC studies represents one important mechanism of improved anti-tumor efficacy associated with co-administration of LMWH and Dox.
New challenges for active reflectarrays (2009)

Active reflect-arrays have proven to be candidates with strong assets as low cost and high performance phased array antennas. THALES Systemes Aeroportes has been developing for some years a concept based on a wave-guide phase shifting cell and applied for various applications in X band. Recent and future applications necessitate improved performances, hence requiring new developments in technique, technology and simulation models. Some of these new challenges are presented here.
Multiscale structural characterizations of mixed U(iv)–An(iii) oxalates (An(iii) = Pu or Am) combining XAS and XRD measurements (2016)

Mixed actinide(III,IV) oxalates of the general formula M2.2UAn(C2O4)5·nH2O (An = Pu or Am and M = H3O(+) and N2H5(+)) have been quantitatively precipitated by oxalic precipitation in nitric acid medium (yield >99%). Thorough multiscale structural characterization using XRD and XAS measurements confirmed the existence of mixed actinide oxalate solid solutions. The XANES analysis confirmed that the oxidation states of the metallic cations, tetravalent for uranium and trivalent for plutonium and americium, are maintained during the precipitation step. EXAFS measurements show that the local environments around U(+IV), Pu(+III) and Am(+III) are comparable, and the actinides are surrounded by ten oxygen atoms from five bidentate oxalate anions. The mean metal-oxygen distances obtained by XAS measurements are in agreement with those calculated from XRD lattice parameters.
Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1 (2002)

Chronic lymphocytic leukemia (CLL) B cells have defects in apoptosis pathways and therefore accumulate in vivo. However, when removed from the patient and cultured in vitro, these malignant cells rapidly undergo apoptosis. Recent studies suggest that leukemia cell survival is influenced by interactions with nonleukemia cells in the microenvironment of lymph nodes, marrow, and other tissues. To model such cell-cell interactions in vitro, we cultured freshly isolated CLL B cells with a follicular dendritic cell line, HK. CLL B cells cocultured with HK cells were protected from apoptosis, either spontaneous or induced by treatment with anticancer drugs. Protection against spontaneous apoptosis could also be induced by coculturing the CLL B cells with normal dendritic cells (DCs) or with a CD40-ligand (CD154)-expressing fibroblast cell line. Examination of the expression of several apoptosis-regulatory proteins revealed that coculture with HK cells or DCs induced up-regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in CLL B cells, whereas CD40 ligation increased expression of Bcl-X(L). Cell-cell contact was required for HK-induced protection, and introducing neutralizing antibodies against various adhesion molecules showed that CD44 was involved in HK-mediated survival, whereas CD40, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were not. Anti-CD44 antibodies also blocked Mcl-1 induction by HK cells. Mcl-1 antisense oligonucleotides reduced leukemia cell expression of Mcl-1, and significantly suppressed HK-induced protection against apoptosis, whereas control oligonucleotides had no effect. Thus, HK cells protect CLL B cells against apoptosis, at least in part through a CD44-dependent mechanism involving up-regulation of Mcl-1, and this mechanism is distinct from that achieved by CD40 ligation. Consequently, the particular antiapoptotic proteins important for CLL survival may vary depending on the microenvironment.
Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. (1992)

To determine the organ distribution of production of the three endothelin (ET) isopeptides, we have developed three ribonuclease protection assays specific for the messenger RNAs (mRNAs) of rat ETs 1, 2, and 3.12 organs from adult Sprague-Dawley rats were examined: heart, lung, liver, spleen, kidney, stomach, small intestine, large intestine, testis, muscle, salivary gland, and brain. The mRNA for ET1 was five times more abundant in the lung than in any other organ studied, moderate expression was seen in the large intestine, and lower levels of mRNA were detected in each of the other organs examined. ET2 was expressed at high level in both large and small intestine and at low level in stomach, muscle, and heart, but ET2 mRNA could not be detected elsewhere. ET3 mRNA was found in all organs, particularly in small intestine, lung, kidney, and large intestine. Because of reports suggesting that ETs might be involved in the hypoperfusion and hypofiltration observed in postischemic kidneys, we have also studied levels of mRNA in kidneys that had previously been subjected to 25 or 45 min of clamping of the renal pedicle. At 6 h after 45 min of ischemia, ET1 mRNA increased to a peak of 421 +/- 69% (mean +/- SEM, n = 3) of that in a standard renal RNA preparation. By contrast, ET3 mRNA decreased in the postischemic organ, falling to a value of 19 +/- 2% of standard at the same time point. The effects of ischemia on ET1 and ET3 mRNAs were long-lasting, with elevation of ET1 and depression of ET3 persisting for days. ET2 mRNA remained undetectable throughout. These findings (a) support a role for ET1 in postischemic renal vascular phenomena and (b) demonstrate a situation in which the expression of ET isoforms is clearly subject to differential regulation.
Stereoselective Synthesis of Enantiomerically Pure Drugs (2000)

This chapter contains sections titled: Introduction Classification of the Methods for the Preparation of Enantiomerically Pure Compounds Examples of Stereoselective Synthesis of Drugs Outlook and Conclusions
Ambient-Pressure XPS Study of GeO2/Ge(100) and SiO2/Si(100) at Controlled Relative Humidity (2014)

Ambient-pressure X-ray photoelectron spectroscopy is used to unveil the water uptake of a thin GeO 2 film on Ge(100) as well as its effect on the electronic properties of the oxide film. We also compare these results with those for a SiO 2 /Si(100) sample. We detect significant positive charging of the GeO 2 film once it is exposed to water vapor even at a low relative humidity (RH) of approximately 10 -4 %. We also show that the amount of adsorbed water is much larger on GeO 2 than on SiO 2 at RH above 10 -4 %, probably due to the permeability of GeO 2 . Two possible mechanisms are proposed to explain such water-induced positive charging of the GeO 2 film.
Multi-antigen recognition circuits overcome challenges of specificity, heterogeneity, and durability in T cell therapy for glioblastoma (2021)

ABSTRACT Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of target antigens that are both tumor-specific and homogeneously expressed. We show that multiantigen prime-and-kill recognition circuits have the flexibility and precision to overcome these challenges in attacking glioblastoma. A synNotch receptor that recognizes a specific priming antigen – the heterogeneous glioblastoma neoantigen EGFRvIII or a brain tissue-specific antigen – is used to locally induce expression of a CAR, enabling thorough but controlled tumor killing by targeting of homogeneous antigens that are not absolutely tumor specific. Moreover, regulated CAR expression maintains a higher fraction of the T cells in the naïve-like state which is associated with higher durability in vivo . In summary, using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
Cyclization of (−)-Pregaliellalactone in the Fungus Galiella rufa (2002)

Eine intramolekulare Diels-Alder-Reaktion mit inversem Elektronenbedarf in einer Polyketidbiosynthese, bei der in vivo die Cyclisierungsgeschwindigkeit erhöht wird, wird hier vorgestellt. Lebende Mycelien des Pilzes Galiella rufa katalysieren die Cyclisierung von (−)-Pregaliellalacton 1 zu (+)-Desoxygaliellalacton 2, während tote Mycelien keine Wirkung haben. Mit dem nichtnatürlichen Enantiomer (+)-1 war keine Geschwindigkeitserhöhung festzustellen.
Metabolic and cardiovascular effects of TX-001HR in menopausal women with vasomotor symptoms (2019)

<b>Objective:</b> This study aimed to evaluate the effects of TX-001HR (17β-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes. <b>Methods:</b> Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized. <b>Results:</b> A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1-4%, 6-11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population. <b>Conclusions:</b> In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.
The Role of Coronary Microvascular Function and Rotational Deformation Delay in the Development of Increased Left Ventricular Torsion in Uncomplicated Type 1 Diabetes (2009)

The parkinsonism dementia complex of Guam (bodig disease) is characterized by severe neurofibrillary tangle (NFT) development without the senile plaques which characterize Alzheimer's disease. Here we analyze eight cases of bodig and three control cases from Guam, for the numbers of unaffected pyramidal neurons, intracellular NFTs (iNFTs), and extracellular NFTs (eNFTs) in hippocampal sectors CA1 and CA4. We utilized Alz50 immunostaining to identify iNFTs, amyloid P immunostaining to identify eNFTs, and cresyl violet staining to identify the surviving pyramidal neurons. We developed a modification of the Bielschowsky silver staining method which distinguished iNFTs from eNFTs and found the numbers of iNFTs and eNFTs identified by this method to be comparable to those obtained by immunohistochemical staining. In CA4, the combined total of unaffected pyramidal neurons, iNFTs and eNFTs was found to be remarkably constant in all the cases studied. The density of eNFTs correlated significantly and negatively with the density of surviving neurons, which included unaffected neurons and iNFTs. CA1 was more intensely affected than CA4. The combined total of unaffected pyramidal neurons, iNFTs and eNFTs was still relatively constant, although greater variability was recorded. Our results suggest that loss of pyramidal neurons is proportional to the appearance of eNFTs. The eNFTs accumulate, without evidence of disappearance through phagocytosis.
Abstract 3401: Vemurafenib-induced RhoB expression leads to melanoma cell resistance. (2013)

Abstract Most of melanoma harbour mutations leading to the constitutive activation of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (i.e: activating mutations of BRAF, NRAS, c-KIT). Addiction of melanoma to the MAPK pathways led to the development of inhibitors targeting either mutant BRAF, such as Vemurafenib (PLX4032), or MEK. Melanoma treatment recently met a breakthrough with the clinical evaluation of Vemurafenib that demonstrated an unprecedented 80% response rate among patients with BRAF V600E melanomas treated with Vemurafenib, but rapidly limited by drug resistance, which still requires to be elucidated. The MAPK pathway regulates the expression of many genes which can mediate therapeutic response but also resistance, such as RhoGTPases. We analysed the mRNA expression of the RhoGTPases in two BRAF mutated melanoma cell lines, WM266-4 and A375, in response to inhibition of the MAPK pathway by PLX4032. We observed that the mRNA of RhoB was increased by PLX4032 treatment. This result was confirmed in many other BRAF mutated melanoma cell lines by inhibition of the MAPK pathway with BRAF inhibitors (PLX4032 or SB-590885) as well as MEK inhibitors (AZD6244 or AS703026). MEK inhibitors (AZD6244 or AS703026) upregulate RhoB in BRAF wild-type melanoma cells harbouring N-Ras, K-Ras or c-KIT mutation suggesting that inhibiting MAPK pathway is critical for RhoB expression modulation. It is noteworthy that this modulation is cell type dependent, while it was not found in BRAF mutated non-melanoma cells as colon carcinoma cells (Colo205 and RKO). To investigate the role of RhoB induction in cellular responses to BRAF and MEK inhibitors, the RhoB induction was suppressed using RNA interference. The cells treated with siRNA targeting RhoB, WM266-4 and A375 cells, were more sensitive to PLX4032 and AZD6244. Moreover the blockade of RhoB induction led to a significant increase of PLX4032-induced apoptosis as shown by the increase of the subG1 population and PARP cleavage. Our findings show that RhoB upregulation is involved in PLX4032 response and both inhibitions of MAPK pathway and RhoB expression trigger cell death and should prompt a search for agents. Indeed co-targeting MAPK and RhoB pathways, could lead to a synthetic lethality and prevent resistance to either BRAF or MEK inhibitors. Ongoing work focuses on confirming this role in tumour-xenografted mouse models. Citation Format: Audrey Delmas, Julia Cherier, Claire Medale-Giamarchi, Anne Pradines, Gilles Favre. Vemurafenib-induced RhoB expression leads to melanoma cell resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3401. doi:10.1158/1538-7445.AM2013-3401
Impact of Amino Acid Mutations in PB2, PB1-F2, and NS1 on the Replication and Pathogenicity of Pandemic (H1N1) 2009 Influenza Viruses (2011)

Here, we assessed the effects of PB1-F2 and NS1 mutations known to increase the pathogenicity of influenza viruses on the replication and pathogenicity in mice of pandemic (H1N1) 2009 influenza viruses. We also characterized viruses possessing a PB1-F2 mutation that was recently identified in pandemic (H1N1) 2009 influenza virus isolates, with and without simultaneous mutations in PB2 and NS1. Our results suggest that some NS1 mutations and the newly identified PB1-F2 mutation have the potential to increase the replication and/or pathogenicity of pandemic (H1N1) 2009 influenza viruses.
ChemInform Abstract: The Discovery and Synthesis of Highly Potent, A2a Receptor Agonists. (2000)

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.