8,295 results on '"Schaefer A"'
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2. An Undergraduate Chemistry Lab Exploring Computational Cost and Accuracy: Methane Combustion Energy
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Wolf, Mark E., Norris, J. Widener, Fynewever, Herb, Turney, Justin M., and Schaefer, Henry F., III
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Over the past half century, computational chemistry has evolved from a niche field to a ubiquitous pillar of modern chemical research. Driven by the increased demand for computational chemistry in research settings, the undergraduate curriculum has evolved alongside to ensure that students are well-equipped for modern research. Toward this end, many excellent computational chemistry exercises have been developed that aim to teach students what kinds of questions computational chemistry can answer and how to properly interpret the results. However, there has been far less attention given to the complexities of determining how reliable computational results are and how constraining computational scaling can be. We present an undergraduate lab exercise that uses ab initio methods to predict the combustion energy of methane. The exercise walks students through the process of benchmarking errors on a small system (methane), estimating the computational cost to perform the same analysis on a larger system (propane), and justifying an affordable yet accurate method for a hypothetical study of the larger system. Furthermore, students are introduced to other cost-saving measures like basis set extrapolation and additive corrections. The entire exercise is intentionally designed to require little technical knowledge of computational chemistry and to be flexibly grafted into a standard undergraduate curriculum. In order to ensure accessibility, the exercise utilizes the free open source software Psi4 (available on any operating system) and provides a detailed installation and use guide for completing this lab. This lab will provide students the understanding of how to properly judge, select, and justify different computational models where cost and accuracy compete, a highly desirable set of skills that generalize to any computational science.
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- 2022
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3. Student-Friendly Guide to Molecular Integrals
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Murphy, Kevin V., Turney, Justin M., and Schaefer, Henry F., III
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Preceding even the Hartree-Fock method, molecular integrals are the very foundation upon which quantum chemical molecular modeling depends. Discussions of molecular integrals are normally found only in advanced and technical texts or articles. The objective of the present article is to provide less experienced readers, or students in a physical/computational chemistry course, a thorough understanding of molecular integrals. Through a series of detailed Handouts, the student/reader can participate in the derivation of molecular integrals, and in turn implement them in computer code. Hartree-Fock theory is discussed in enough detail to motivate the molecular integrals and address such topics as the atomic orbital basis. An introduction to the programming language of choice, Python3, is provided, tailored toward developing the essential skills necessary for implementing molecular integrals. The article is intended to be useful not only to instructors of physical/computational chemistry, but also to any reader who has independently sought a primer on this elusive subject.
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- 2018
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4. Overview: quasi-Lagrangian observations of Arctic air mass transformations – introduction and initial results of the HALO–(𝒜 𝒞)3 aircraft campaign
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M. Wendisch, S. Crewell, A. Ehrlich, A. Herber, B. Kirbus, C. Lüpkes, M. Mech, S. J. Abel, E. F. Akansu, F. Ament, C. Aubry, S. Becker, S. Borrmann, H. Bozem, M. Brückner, H.-C. Clemen, S. Dahlke, G. Dekoutsidis, J. Delanoë, E. De La Torre Castro, H. Dorff, R. Dupuy, O. Eppers, F. Ewald, G. George, I. V. Gorodetskaya, S. Grawe, S. Groß, J. Hartmann, S. Henning, L. Hirsch, E. Jäkel, P. Joppe, O. Jourdan, Z. Jurányi, M. Karalis, M. Kellermann, M. Klingebiel, M. Lonardi, J. Lucke, A. E. Luebke, M. Maahn, N. Maherndl, M. Maturilli, B. Mayer, J. Mayer, S. Mertes, J. Michaelis, M. Michalkov, G. Mioche, M. Moser, H. Müller, R. Neggers, D. Ori, D. Paul, F. M. Paulus, C. Pilz, F. Pithan, M. Pöhlker, V. Pörtge, M. Ringel, N. Risse, G. C. Roberts, S. Rosenburg, J. Röttenbacher, J. Rückert, M. Schäfer, J. Schaefer, V. Schemann, I. Schirmacher, J. Schmidt, S. Schmidt, J. Schneider, S. Schnitt, A. Schwarz, H. Siebert, H. Sodemann, T. Sperzel, G. Spreen, B. Stevens, F. Stratmann, G. Svensson, C. Tatzelt, T. Tuch, T. Vihma, C. Voigt, L. Volkmer, A. Walbröl, A. Weber, B. Wehner, B. Wetzel, M. Wirth, and T. Zinner
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Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Global warming is amplified in the Arctic. However, numerical models struggle to represent key processes that determine Arctic weather and climate. To collect data that help to constrain the models, the HALO–(𝒜𝒞)3 aircraft campaign was conducted over the Norwegian and Greenland seas, the Fram Strait, and the central Arctic Ocean in March and April 2022. The campaign focused on one specific challenge posed by the models, namely the reasonable representation of transformations of air masses during their meridional transport into and out of the Arctic via northward moist- and warm-air intrusions (WAIs) and southward marine cold-air outbreaks (CAOs). Observations were made over areas of open ocean, the marginal sea ice zone, and the central Arctic sea ice. Two low-flying and one long-range, high-altitude research aircraft were flown in colocated formation whenever possible. To follow the air mass transformations, a quasi-Lagrangian flight strategy using trajectory calculations was realized, enabling us to sample the same moving-air parcels twice along their trajectories. Seven distinct WAI and 12 CAO cases were probed. From the quasi-Lagrangian measurements, we have quantified the diabatic heating/cooling and moistening/drying of the transported air masses. During CAOs, maximum values of 3 K h−1 warming and 0.3 g kg−1 h−1 moistening were obtained below 1 km altitude. From the observations of WAIs, diabatic cooling rates of up to 0.4 K h−1 and a moisture loss of up to 0.1 g kg−1 h−1 from the ground to about 5.5 km altitude were derived. Furthermore, the development of cloud macrophysical (cloud-top height and horizontal cloud cover) and microphysical (liquid water path, precipitation, and ice index) properties along the southward pathways of the air masses were documented during CAOs, and the moisture budget during a specific WAI event was estimated. In addition, we discuss the statistical frequency of occurrence of the different thermodynamic phases of Arctic low-level clouds, the interaction of Arctic cirrus clouds with sea ice and water vapor, and the characteristics of microphysical and chemical properties of Arctic aerosol particles. Finally, we provide a proof of concept to measure mesoscale divergence and subsidence in the Arctic using data from dropsondes released during the flights.
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- 2024
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5. Development and Evaluation of a Prep Course for Chemistry Graduate Teaching Assistants at a Research University
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Marbach-Ad, Gili, Schaefer, Kathryn L., and Kumi, Bryna C.
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This study describes the development and evaluation of a prep course for chemistry graduate teaching assistants (GTAs). The course was developed around three major goals: (i) building a community for new GTAs and socializing them into the department; (ii) modeling teaching with well-documented, innovative teaching and learning techniques; and (iii) helping GTAs to understand their roles within the department and their specific course. The program consisted of a team-taught, six-week course, which was mandatory for first-year GTAs. It was first offered in Fall 2009 (46 students), and then taught again in Fall 2010 (33 students). The course covered multiple topics including student-GTA communication, student assessment, and teaching strategies. End-of-semester surveys, student evaluations of teaching, and interviews with GTAs were used to evaluate the course. Overall, feedback from the course was very positive. GTAs reported that the course benefited them immediately and even more so after they had taught for several semesters. Student evaluations of teaching showed that, on average, first-year GTAs that had completed the prep course in Fall 2009 and Fall 2010 received significantly higher scores than the previous cohort of new GTAs (who had not completed a prep course) on measures such as effective teaching, respecting students, and being prepared. (Contains 6 tables and 1 figure.)
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- 2012
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6. The Use of Gas Chromatography and Mass Spectrometry to Introduce General Chemistry Students to Percent Mass and Atomic Mass Calculations
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Pfennig, Brian W. and Schaefer, Amy K.
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A general chemistry laboratory experiment is described that introduces students to instrumental analysis using gas chromatography-mass spectrometry (GC-MS), while simultaneously reinforcing the concepts of mass percent and the calculation of atomic mass. Working in small groups, students use the GC to separate and quantify the percent composition in a mixture of dichloromethane and chloroform dissolved in toluene by the injection of known quantities of each pure substance dissolved in toluene and the determination of the individual instrumental response factor. The relative abundances of the chlorine-35 and chlorine-37 isotopes can also be determined from several different groupings on the mass spectra of the compounds, allowing for the calculation of the atomic mass of chlorine. This collaborative-learning experiment enhances student understanding through the hands-on use of chemical instrumentation and helps to develop their problem solving skills in the analysis of several different types of experimental data. (Contains 3 tables and 3 figures.)
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- 2011
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7. Promoting Student Learning through Group Problem Solving in General Chemistry Recitations
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Mahalingam, Madhu, Schaefer, Fr, and Morlino, Elisabeth
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We describe the implementation and effects of group problem solving in recitation sections associated with the general chemistry course at a small private science university. Recitation sections of approximately 45 students are used to supplement large (approximately 180 students) lecture sections. The primary goal of recitation is working in small groups to solve problems in an environment that is designed to foster collaboration and discussion among group members. Students are placed in groups of mixed-ability based on SAT mathematics scores. The model of using heterogeneous groups was adopted as weaker students benefit by posing questions to students with stronger skills and stronger students benefit from verbalizing their ideas. Student response to the implementation has been positive. Exam averages have improved since the introduction of the group work. We show that it is possible to improve student learning through implementation of structured group work in a large general chemistry course with minimal changes in faculty hours and facility space. (Contains 1 figure and 3 tables.)
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- 2008
8. Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors
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Florian Wittlinger, Blessing C. Ogboo, Ekaterina Shevchenko, Tahereh Damghani, Calvin D. Pham, Ilse K. Schaeffner, Brandon T. Oligny, Surbhi P. Chitnis, Tyler S. Beyett, Alexander Rasch, Brian Buckley, Daniel A. Urul, Tatiana Shaurova, Earl W. May, Erik M. Schaefer, Michael J. Eck, Pamela A. Hershberger, Antti Poso, Stefan A. Laufer, and David E. Heppner
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Chemistry ,QD1-999 - Abstract
Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.
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- 2024
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9. Targeting the High-Density Lipoprotein Proteome for the Treatment of Post-Acute Sequelae of SARS-CoV-2
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Karsten Grote, Ann-Christin Schaefer, Muhidien Soufi, Volker Ruppert, Uwe Linne, Aditya Mukund Bhagwat, Witold Szymanski, Johannes Graumann, Yana Gercke, Sümeya Aldudak, Denise Hilfiker-Kleiner, Elisabeth Schieffer, and Bernhard Schieffer
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post-COVID-19 ,case series ,cholesterol metabolism ,drug therapy ,proteomics ,HDL proteome ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Here, we target the high-density lipoprotein (HDL) proteome in a case series of 16 patients with post-COVID-19 symptoms treated with HMG-Co-A reductase inhibitors (statin) plus angiotensin II type 1 receptor blockers (ARBs) for 6 weeks. Patients suffering from persistent symptoms (post-acute sequelae) after serologically confirmed SARS-CoV-2 infection (post-COVID-19 syndrome, PCS, n = 8) or following SARS-CoV-2 vaccination (PVS, n = 8) were included. Asymptomatic subjects with corresponding serological findings served as healthy controls (n = 8/8). HDL was isolated using dextran sulfate precipitation and the HDL proteome of all study participants was analyzed quantitatively by mass spectrometry. Clinical symptoms were assessed using questionnaires before and after therapy. The inflammatory potential of the patients’ HDL proteome was addressed in human endothelial cells. The HDL proteome of patients with PCS and PVS showed no significant differences; however, compared to controls, the HDL from PVS/PCS patients displayed significant alterations involving hemoglobin, cytoskeletal proteins (MYL6, TLN1, PARVB, TPM4, FLNA), and amyloid precursor protein. Gene Ontology Biological Process (GOBP) enrichment analysis identified hemostasis, peptidase, and lipoprotein regulation pathways to be involved. Treatment of PVS/PCS patients with statins plus ARBs improved the patients’ clinical symptoms. After therapy, three proteins were significantly increased (FAM3C, AT6AP2, ADAM10; FDR < 0.05) in the HDL proteome from patients with PVS/PCS. Exposure of human endothelial cells with the HDL proteome from treated PVS/PCS patients revealed reduced inflammatory cytokine and adhesion molecule expression. Thus, HDL proteome analysis from PVS/PCS patients enables a deeper insight into the underlying disease mechanisms, pointing to significant involvement in metabolic and signaling disturbances. Treatment with statins plus ARBs improved clinical symptoms and reduced the inflammatory potential of the HDL proteome. These observations may guide future therapeutic strategies for PVS/PCS patients.
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- 2024
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10. Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs
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Gershon A. K. Mensah, Katherine G. Schaefer, Michael G. Bartlett, Arthur G. Roberts, and Gavin M. King
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membrane protein ,lipid bilayer ,nuclear magnetic resonance spectroscopy ,force microscopy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein’s activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: ‘open-inward’, ‘open-outward’, and ‘intermediate’. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein’s tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent ‘open-outward’ conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs.
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- 2023
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11. Integrative Plasma Metabolic and Lipidomic Modelling of SARS-CoV-2 Infection in Relation to Clinical Severity and Early Mortality Prediction
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Samantha Lodge, Nathan G. Lawler, Nicola Gray, Reika Masuda, Philipp Nitschke, Luke Whiley, Sze-How Bong, Bu B. Yeap, Girish Dwivedi, Manfred Spraul, Hartmut Schaefer, Rubén Gil-Redondo, Nieves Embade, Oscar Millet, Elaine Holmes, Julien Wist, and Jeremy K. Nicholson
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COVID-19 ,SARS-CoV-2 ,NMR spectroscopy ,mass spectrometry ,plasma IVDr ,metabolomics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
An integrative multi-modal metabolic phenotyping model was developed to assess the systemic plasma sequelae of SARS-CoV-2 (rRT-PCR positive) induced COVID-19 disease in patients with different respiratory severity levels. Plasma samples from 306 unvaccinated COVID-19 patients were collected in 2020 and classified into four levels of severity ranging from mild symptoms to severe ventilated cases. These samples were investigated using a combination of quantitative Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS) platforms to give broad lipoprotein, lipidomic and amino acid, tryptophan-kynurenine pathway, and biogenic amine pathway coverage. All platforms revealed highly significant differences in metabolite patterns between patients and controls (n = 89) that had been collected prior to the COVID-19 pandemic. The total number of significant metabolites increased with severity with 344 out of the 1034 quantitative variables being common to all severity classes. Metabolic signatures showed a continuum of changes across the respiratory severity levels with the most significant and extensive changes being in the most severely affected patients. Even mildly affected respiratory patients showed multiple highly significant abnormal biochemical signatures reflecting serious metabolic deficiencies of the type observed in Post-acute COVID-19 syndrome patients. The most severe respiratory patients had a high mortality (56.1%) and we found that we could predict mortality in this patient sub-group with high accuracy in some cases up to 61 days prior to death, based on a separate metabolic model, which highlighted a different set of metabolites to those defining the basic disease. Specifically, hexosylceramides (HCER 16:0, HCER 20:0, HCER 24:1, HCER 26:0, HCER 26:1) were markedly elevated in the non-surviving patient group (Cliff’s delta 0.91–0.95) and two phosphoethanolamines (PE.O 18:0/18:1, Cliff’s delta = −0.98 and PE.P 16:0/18:1, Cliff’s delta = −0.93) were markedly lower in the non-survivors. These results indicate that patient morbidity to mortality trajectories is determined relatively soon after infection, opening the opportunity to select more intensive therapeutic interventions to these “high risk” patients in the early disease stages.
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- 2023
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12. Mesenchymal Stem Cells in Nerve Tissue Engineering: Bridging Nerve Gap Injuries in Large Animals
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Mirko Lischer, Pietro G. di Summa, Ilias G. Petrou, Dirk J. Schaefer, Raphael Guzman, Daniel F. Kalbermatten, and Srinivas Madduri
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cell therapy ,large animal models ,nerve injury ,nerve regeneration ,nerve guidance conduit ,Schwann cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cell-therapy-based nerve repair strategies hold great promise. In the field, there is an extensive amount of evidence for better regenerative outcomes when using tissue-engineered nerve grafts for bridging severe gap injuries. Although a massive number of studies have been performed using rodents, only a limited number involving nerve injury models of large animals were reported. Nerve injury models mirroring the human nerve size and injury complexity are crucial to direct the further clinical development of advanced therapeutic interventions. Thus, there is a great need for the advancement of research using large animals, which will closely reflect human nerve repair outcomes. Within this context, this review highlights various stem cell-based nerve repair strategies involving large animal models such as pigs, rabbits, dogs, and monkeys, with an emphasis on the limitations and strengths of therapeutic strategy and outcome measurements. Finally, future directions in the field of nerve repair are discussed. Thus, the present review provides valuable knowledge, as well as the current state of information and insights into nerve repair strategies using cell therapies in large animals.
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- 2023
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13. Arsenite Exposure to Human RPCs (HRTPT) Produces a Reversible Epithelial Mesenchymal Transition (EMT): In-Vitro and In-Silico Study
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Sonalika Singhal, Scott H. Garrett, Seema Somji, Kalli Schaefer, Benu Bansal, Jappreet Singh Gill, Sandeep K. Singhal, and Donald A. Sens
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inorganic arsenic ,bioinformatics ,kidney ,nephrotoxicity ,EMT ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.
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- 2023
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14. Opposing MMP-9 Expression in Mesenchymal Stromal Cells and Head and Neck Tumor Cells after Direct 2D and 3D Co-Culture
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Anna Waltera, Daniela Schulz, Nicole Schaefer, Sabine Stoeckl, Eric Pion, Silke Haerteis, Torsten E. Reichert, Tobias Ettl, and Richard J. Bauer
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HNSCC ,head and neck cancer ,BMSC ,bone marrow-derived stromal cells ,angiogenesis ,MMP ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. In our experiments, direct 3D co-culture of BMSCs with tumor cells from the head and neck region (HNSCC) results in strong expression and secretion of MMP-9. The observed MMP-9 secretion mainly originates from BMSCs, leading to increased invasiveness. In addition to our in vitro data, we show in vivo data based on the chorioallantoic membrane (CAM) model. Our results demonstrate that MMP-9 induces hemorrhage and increased perfusion in BMSC/HNSCC co-culture. While we had previously outlined that MMP-9 expression and secretion originate from BMSCs, our data showed a strong downregulation of MMP-9 promoter activity in HNSCC cells upon direct contact with BMSCs using the luciferase activity assay. Interestingly, the 2D and 3D models of direct co-culture suggest different drivers for the downregulation of MMP-9 promoter activity. Whereas the 3D model depicts a BMSC-dependent downregulation, the 2D model shows cell density-dependent downregulation. In summary, our data suggest that the direct interaction of HNSCC cells and BMSCs promotes tumor progression by significantly facilitating angiogenesis via MMP-9 expression. On the other hand, data from 3D and 2D co-culture models indicate opposing regulation of the MMP-9 promoter in tumor cells once stromal cells are involved.
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- 2023
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15. Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet
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Ariane Zaloszyc, Philippe Choquet, Amira Sayeh, Maria Bartosova, Betti Schaefer, Ulrike Huegel, Gaëlle Aubertin-Kirch, Christopher Healy, François Severac, Sébastien Rizzo, Georges Boivin, Franz Schaefer, Michel Fischbach, Justine Bacchetta, Seiamak Bahram, and Claus Peter Schmitt
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preclinical studies ,parathyroid related disorder ,CKD-MBD ,bone scintigraphy ,bone μCT ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gαs/PKA and the Gαq/11/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gαq/11 knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gαq/11 KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gαq/11 KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gαq/11 KO mice had similar bone morphology compared to WT, while CKD Gαq/11-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gαq/11-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gαq/11-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gαq/11/PKC KO further aggravates mineral bone disease.
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- 2022
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16. Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm
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Thomas Aschacher, Daniela Geisler, Verena Lenz, Olivia Aschacher, Bernhard Winkler, Anne-Kristin Schaefer, Andreas Mitterbauer, Brigitte Wolf, Florian K. Enzmann, Barbara Messner, Günther Laufer, Marek P. Ehrlich, Martin Grabenwöger, and Michael Bergmann
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telomere ,aneurysm ,DNA damage ,senescence-associated secretory phenotype ,cell death ,thoracic aorta ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.
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- 2022
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17. Episignature Mapping of TRIP12 Provides Functional Insight into Clark–Baraitser Syndrome
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Liselot van der Laan, Kathleen Rooney, Mariëlle Alders, Raissa Relator, Haley McConkey, Jennifer Kerkhof, Michael A. Levy, Peter Lauffer, Mio Aerden, Miel Theunis, Eric Legius, Matthew L. Tedder, Lisenka E. L. M. Vissers, Saskia Koene, Claudia Ruivenkamp, Mariette J. V. Hoffer, Dagmar Wieczorek, Nuria C. Bramswig, Theresia Herget, Vanesa López González, Fernando Santos-Simarro, Pernille M. Tørring, Anne-Sophie Denomme-Pichon, Bertrand Isidor, Boris Keren, Sophie Julia, Elise Schaefer, Christine Francannet, Pierre-Yves Maillard, Mala Misra-Isrie, Hilde Van Esch, Marcel M. A. M. Mannens, Bekim Sadikovic, Mieke M. van Haelst, and Peter Henneman
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TRIP12 ,Clark–Baraitser syndrome ,intellectual disability ,DNA methylation ,episignature ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark–Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
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- 2022
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18. In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome
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Zhihuang Zheng, Yao Xu, Ute Krügel, Michael Schaefer, Tilman Grune, Bernd Nürnberg, May-Britt Köhler, Maik Gollasch, Dmitry Tsvetkov, and Lajos Markó
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TRPC6 ,UUO ,NZO mice ,inflammation ,fibrosis ,CKD ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.
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- 2022
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19. Intraoperative electromagnetic navigation bronchoscopy (IENB) to localize peripheral lung lesions: A new technique in the pediatric oncology population
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Marc S. Arkovitz, F. Dylan Stewart, Kassem Harris, Edo Schaefer, and Jeremy Rosenblum
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medicine.medical_specialty ,Lung Neoplasms ,Population ,chemistry.chemical_compound ,Bronchoscopy ,Biopsy ,Pediatric oncology ,medicine ,Humans ,Child ,education ,Lung ,Retrospective Studies ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Solitary Pulmonary Nodule ,General Medicine ,Peripheral ,medicine.anatomical_structure ,chemistry ,Pediatrics, Perinatology and Child Health ,Surgery ,Radiology ,business ,Electromagnetic Phenomena ,Indocyanine green ,Electromagnetic navigation bronchoscopy ,Pediatric population - Abstract
Background : The utility, diagnostic yield and accuracy of lung biopsies in pediatric oncology patients are variable. Here we describe our preliminary results using intraoperative electromagnetic navigation bronchoscopy (IENB) for peripheral lung lesions to increase the surgical yield and accuracy in pediatric oncology patients. Methods : From May 2018 until October 2020 all surgical lung biopsies on pediatric oncology patients were performed using IENB technology. IENB and tattooing with methylene blue dye, Indocyanine green dye or both followed by Video-assisted Thoracoscopic Surgery (VATS) was performed in the same setting. Data were collected retrospectively. Data points included diagnosis, technical success, pathologic diagnosis and alteration in treatment management and complications. Results : A total of 10 biopsy procedures were performed on 8 patients during the study. The youngest patient was 7 years old. All had successful IENB with tattooing. All biopsies were diagnostic. No procedures were converted to open. There were no technical failures or procedure complications. One patient had a total of 11 biopsies, 6 from the right lung and 5 from the left, performed at 2 separate procedures. Another had 2 biopsies, one from the right lung and one from the left performed at the same operation. In 7 of the 8 patients treatment changes were made based on results of their biopsy. Conclusion : Here we present the first described experience of IENB and tattooing of peripheral lung lesions in the pediatric population. We have shown that IENB for peripheral lung lesion localization is a safe and effective technique in pediatric oncology.
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- 2022
20. Linear dicoordinate beryllium: a [.sup.9]Be solid-state NMR study of a discrete zero-valent s-block beryllium complex
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Leroy, C., Schuster, J.K., Schaefer, T., Muller-Buschbaum, K., Braunschweig, H., and Bryce, D.L.
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Nuclear magnetic resonance spectroscopy -- Methods ,Beryllium -- Chemical properties ,Chemistry - Abstract
Beryllium-9 ([.sup.9]Be) quadrupolar coupling and chemical shift tensor data are reported for bis(1-(2,6-diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidine-2-ylidene)beryllium (Be[(CAAC).sub.2]). These are the first such data for beryllium in a linear dicoordinate environment. The [.sup.9]Be quadrupolar coupling constant, 2.36(0.02) MHz, is the largest recorded in the solid state to date for this isotope. The span of the beryllium chemical shift tensor, 22(2) ppm, covers about half of the known [.sup.9]Be chemical shift range, and the isotropic [.sup.9]Be chemical shift, 32.0(0.3) ppm, is the largest reported in the solid state to our knowledge. DFT calculations reproduce the experimental data well. A natural localized molecular orbital approach has been used to explain 0the origins and orientation of the beryllium electric field gradient tensor. The single-crystal X-ray structure of a second polymorph of Be[(CAAC).sub.2] is also reported. Inspection of the powder X-ray diffraction data shows that the new crystal structure is part of the bulk product next to another crystalline phase. Therefore, experimental X-ray powder data for the microcrystalline powder sample and the SSNMR data do not fully match either the originally reported crystal structure (Arrowsmith et al. Nat. Chem. 2016, 8, 890-894) or the new polymorph. The ability of solid-state NMR and powder X-ray diffraction to characterize powdered samples was thus particularly useful in this work. Key words: beryllium, solid-state NMR, crystal structure. Nous presentons les donnees de couplage quadripolaire et de tenseur de deplacement chimique du beryllium 9 ([.sup.9]Be) pour le bis(1-(2,6-diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidine-2-ylidene)beryllium (Be[(CAAC).sub.2]). Ces donnees sont les pre-mieres du genre a porter sur le beryllium dans un environnement lineaire dicoordonne. La valeur de la constante de couplage quadripolaire du [.sup.9]Be, soit 2,36(0,02) MHz, est la plus grande jamais enregistree a l'etat solide pour cet isotope. L'envergure du tenseur de deplacement chimique du beryllium, soit 22(2) ppm, couvre environ la moitie de l'etendue connue du deplacement chimique du [.sup.9]Be, et le deplacement chimique isotrope du [.sup.9]Be, soit 32,0(0,3) ppm, est a notre connaissance le plus ample jamais rapporte a l'etat solide. Les calculs de DFT concordent bien avec les donnees experimentales. Nous avons employe une approche d'orbitale moleculaire naturelle localisee pour expliquer les origines et l'orientation du tenseur de gradient de champ electrique du beryllium. Nous decrivons egalement la structure d'un second polymorphe du Be[(CAAC).sub.2] obtenue par diffraction des rayons X sur cristal unique. L'examen des donnees de diffraction des rayons X sur poudre (DRXP) revele que la nouvelle structure cristalline fait partie de la matiere adjacente a une autre phase cristalline. Par consequent, les donnees experimentales de DRXP de l'echantillon de poudre microcristalline et les donnees RMN a l'etat solide ne correspondent parfaitement ni a la structure cristalline publiee a l'origine (Arrowsmith et al., Nature Chem. 2016, 8, 890-894) ni au nouveau polymorphe. La possibilite de caracteriser des echantillons sous forme de poudre par RMN a l'etat solide et DRXP nous a donc ete particulierement utile dans le cadre de ces travaux. [Traduit par la Redaction] Mots-cles : beryllium, RMN a l'etat solide, structure crystalline., Introduction Beryllium is an alkaline earth metal that possesses the greatest electronegativity and smallest atomic radius of its family. (1) It is almost exclusively found in complexes with an oxidation [...]
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- 2018
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21. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome
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Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, Anne-Sophie Lebre, Foroutan A., Haghshenas S., Bhai P., Levy M.A., Kerkhof J., McConkey H., Niceta M., Ciolfi A., Pedace L., Miele E., Genevieve D., Heide S., Alders M., Zampino G., Merla G., Fradin M., Bieth E., Bonneau D., Dieterich K., Fergelot P., Schaefer E., Faivre L., Vitobello A., Maitz S., Fischetto R., Gervasini C., Piccione M., van de Laar I., Tartaglia M., Sadikovic B., Lebre A.-S., Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, University of Western Ontario (UWO), London Health Sciences Center (LHSC), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amsterdam UMC - Amsterdam University Medical Center, University of Amsterdam [Amsterdam] (UvA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University of Naples Federico II = Università degli studi di Napoli Federico II, Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy] (FC2S), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), San Gerardo Hospital [Monza, Italy] (SGH), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Palermo - University of Palermo, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Foroutan, A., Haghshenas, S., Bhai, P., Levy, M. A., Kerkhof, J., Mcconkey, H., Niceta, M., Ciolfi, A., Pedace, L., Miele, E., Genevieve, D., Heide, S., Alders, M., Zampino, G., Merla, G., Fradin, M., Bieth, E., Bonneau, D., Dieterich, K., Fergelot, P., Schaefer, E., Faivre, L., Vitobello, A., Maitz, S., Fischetto, R., Gervasini, C., Piccione, M., van de Laar, I., Tartaglia, M., Sadikovic, B., Lebre, A. -S., Martinez Rico, Clara, and Clinical Genetics
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Wiedemann–Steiner syndrome ,QH301-705.5 ,Intellectual disability ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Catalysis ,Inorganic Chemistry ,KMT2A gene ,Neurodevelopmental disorder ,Growth Disorder ,Abnormalities, Multiple ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Biology (General) ,Physical and Theoretical Chemistry ,Episignature ,QD1-999 ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Molecular Biology ,Spectroscopy ,DNA methylation ,Organic Chemistry ,Neurodevelopmental disorders ,Craniofacial Abnormalitie ,Epigenetic ,Hypertrichosi ,General Medicine ,Facie ,Computer Science Applications ,Chemistry ,epigenetics ,episignature ,intellectual disability ,neurodevelopmental disorders ,Phenotype ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Epigenetics ,Human - Abstract
Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
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- 2022
22. Using carbon-14 and carbon-13 measurements for source attribution of atmospheric methane in the Athabasca oil sands region
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Felix Vogel, Regina Gonzalez Moguel, Peter M. J. Douglas, Sébastien Ars, Jocelyn Turnbull, and Hinrich Schaefer
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geography ,Atmospheric Science ,geography.geographical_feature_category ,Atmospheric methane ,Physics ,QC1-999 ,Environmental engineering ,Wetland ,Tailings ,Methane ,chemistry.chemical_compound ,Chemistry ,TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES ,chemistry ,Surface mining ,Oil reserves ,Greenhouse gas ,Environmental science ,Oil sands ,QD1-999 - Abstract
The rapidly expanding and energy-intensive production from the Canadian oil sands, one of the largest oil reserves globally, accounts for almost 12 % of Canada's greenhouse gas emissions according to inventories. Developing approaches for evaluating reported methane (CH4) emission is crucial for developing effective mitigation policies, but only one study has characterized CH4 sources in the Athabasca oil sands region (AOSR). We tested the use of 14C and 13C carbon isotope measurements in ambient CH4 from the AOSR to estimate source contributions from key regional CH4 sources: (1) tailings ponds, (2) surface mines and processing facilities, and (3) wetlands. The isotopic signatures of ambient CH4 indicate that the CH4 enrichments measured at the site were mainly influenced by fossil CH4 emissions from surface mining and processing facilities (56 ± 18 %), followed by fossil CH4 emissions from tailings ponds (34 ± 18 %) and to a lesser extent modern CH4 emissions from wetlands (10 ± CH4 emissions and show that this method can successfully distinguish wetland CH4 emissions. In the future, the isotopic characterization of CH4 sources and measurements from different seasons and wind directions are needed to provide a better source attribution in the AOSR.
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- 2022
23. The rewarding effects of alcohol after bariatric surgery: do they change and are they associated with pharmacokinetic changes?
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Ross D. Crosby, James E. Mitchell, Lauren M. Schaefer, Kristine J. Steffen, Gail A. Kerver, Lynnette M. Leone, Scott G. Engel, Greg T. Smith, and John Gunstad
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medicine.medical_specialty ,Alcohol Drinking ,Gastric bypass ,Gastric Bypass ,Bariatric Surgery ,Alcohol ,Alcohol use disorder ,medicine.disease_cause ,Article ,chemistry.chemical_compound ,Pharmacokinetics ,medicine ,Humans ,Ethanol ,Gastric bypass surgery ,business.industry ,medicine.disease ,United States ,Obesity, Morbid ,Surgery ,Alcoholism ,Increased risk ,chemistry ,Empirical examination ,business ,Weight Loss Surgery - Abstract
BACKGROUND: Research shows that surgery patients who have undergone Roux-en-Y gastric bypass (RYGB) are at increased risk for an alcohol use disorder (AUD). However, the mechanisms through which this increased risk is incurred are poorly understood. A host of variables have been proposed as potentially causal in developing AUDs, but empirical examination of many of these variables in human samples is lacking. OBJECTIVES: Our objective was to examine the extent to which alcohol pharmacokinetics (PK), the rewarding effects of alcohol, and the relationship between these variables change from before to after weight loss surgery. SETTING: Large healthcare facility in the Midwest United States METHODS: Thirty-four participants completed assessments prior to, and one year after, RYGB. They completed laboratory sessions and provided data on the PK of alcohol and the extent to which alcohol was reinforcing to them at each timepoint. RESULTS: Findings show that the PK effects of alcohol (p
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- 2022
24. Learning Design Rules for Selective Oxidation Catalysts from High-Throughput Experimentation and Artificial Intelligence
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Christopher Sutton, Luca M. Ghiringhelli, Lucas Foppa, Sandip De, Matthias Scheffler, Ansgar Schaefer, Stephan Schunk, and Patricia Löser
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Materials science ,chemistry.chemical_element ,General Chemistry ,Tungsten ,Catalysis ,Ruthenium ,Electronegativity ,chemistry.chemical_compound ,chemistry ,Catalytic oxidation ,Chemical engineering ,Reactivity (chemistry) ,Oxygenate ,Acrylic acid - Abstract
The design of heterogeneous catalysts is challenged by the complexity of materials and processes that govern reactivity and by the fact that the number of good catalysts is very small in comparison to the number of possible materials. Here, we show how the subgroup-discovery (SGD) artificial-intelligence approach can be applied to an experimental plus theoretical data set to identify constraints on key physicochemical parameters, the so-called SG rules, which exclusively describe materials and reaction conditions with outstanding catalytic performance. By using high-throughput experimentation, 120 SiO2-supported catalysts containing ruthenium, tungsten, and phosphorus were synthesized and tested in the catalytic oxidation of propylene. As candidate descriptive parameters, the temperature and 10 parameters related to the composition and chemical nature of the catalyst materials, derived from calculated free-atom properties, were offered. The temperature, the phosphorus content, and the composition-weighted electronegativity are identified as key parameters describing high yields toward the value-added oxygenate products acrolein and acrylic acid. The SG rules not only reflect the underlying processes particularly associated with high performance but also guide the design of more complex catalysts containing up to five elements in their composition.
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- 2022
25. Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum
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Philipp Nitschke, Samantha Lodge, Drew Hall, Hartmut Schaefer, Manfred Spraul, Nieves Embade, Oscar Millet, Elaine Holmes, Julien Wist, and Jeremy K. Nicholson
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BLOOD ,Biochemistry ,Analytical Chemistry ,INFECTION ,0399 Other Chemical Sciences ,Electrochemistry ,URINE ,SPECTRA ,Humans ,Environmental Chemistry ,NUCLEAR-MAGNETIC-RESONANCE ,Phospholipids ,Spectroscopy ,Science & Technology ,IDENTIFICATION ,SARS-CoV-2 ,Chemistry, Analytical ,COVID-19 ,PLASMA-LIPOPROTEINS ,GLYCOPROTEINS ,Chemistry ,GLYCA ,Physical Sciences ,H-1-NMR SPECTROSCOPY ,Protons ,0301 Analytical Chemistry ,Biomarkers - Abstract
A JEDI NMR pulse experiment incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quantitatively two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramolecular phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI experiment that strongly attenuate contributions from the other molecular species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) versus SARS-CoV-2 positive patients (n = 29) (p = 5.2 × 10-8 and 3.7 × 10-8 respectively). Simplification of the sample preparation allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min experiment time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex laboratory environment, thus lowering the barrier to clinical translation of this diagnostic technology.
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- 2022
26. Valorisation of 2,5-dimethylfuran over zeolite catalysts studied by on-line FTIR-MS gas phase analysis
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Andreas Schaefer, Christopher Sauer, Anders Lorén, and Per-Anders Carlsson
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chemistry.chemical_compound ,Olefin fiber ,chemistry ,Thermal desorption spectroscopy ,Xylene ,Photochemistry ,Zeolite ,Benzene ,Selectivity ,Toluene ,Catalysis - Abstract
The valorisation of 2,5-dimethylfuran (2,5-dmf) by catalytic fast pyrolysis (CFP) was studied by on-line FTIR-MS gas phase analysis. Zeolite beta, H-ZSM-5 and Cu-ZSM-5 were characterised and used as catalysts. The on-line analysis enables sufficient time resolution to follow subminute transient phenomena, e.g., the impact of catalyst pretreatment and time on stream (TOS) on the reaction selectivity. The results show, that the initial selectivity towards benzene, toluene and xylene (BTX) aromatics is high but decreases with TOS while the isomerisation rates of 2,5-dmf towards 2,4-dimethylfuran and cyclic ketones increase. This indicates the involvement of specific active sites for the different conversion processes. The formation of BTX compounds is linked to the availability of specific olefins, as supported by temperature programmed desorption experiments, which is indicative of aromatisation stemming directly from the olefin pool rather than via Diels–Alder reactions.
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- 2022
27. Instructional Approach to Molecular Electronic Structure Theory
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Dykstra, Clifford E. and Schaefer, Henry F.
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Describes a graduate quantum mechanics projects in which students write a computer program that performs ab initio calculations on the electronic structure of a simple molecule. Theoretical potential energy curves are produced. (MLH)
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- 1977
28. Addressing amorphization and transgranular fracture of B 4 C through Si doping and TiB 2 microparticle reinforcing
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Richard A. Haber, Chawon Hwang, Kelvin Y. Xie, Qi An, William A. Goddard, Jun Du, Kevin J. Hemker, Mark C. Schaefer, Qirong Yang, Jerry C. LaSalvia, Azmi Mert Celik, and Kent Harrison Christian
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chemistry.chemical_compound ,Materials science ,chemistry ,Titanium boride ,Doping ,Materials Chemistry ,Ceramics and Composites ,Transgranular fracture ,Boron carbide ,Composite material ,Microparticle - Published
- 2021
29. In Ovo Testing Method for Inhalants on a Chorio-Allantoic Membrane
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Jan Schulze, Udo Bakowsky, Muhammad Umair Amin, Sabine Agel, Jens Schaefer, and Jennifer Lehmann
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Intoxicative inhalant ,animal structures ,Angiogenesis ,Chemistry ,Biochemistry (medical) ,Biomedical Engineering ,Cancer ,General Chemistry ,Chorio allantoic membrane ,medicine.disease ,In ovo ,Metastasis ,Biomaterials ,embryonic structures ,Cancer research ,medicine - Abstract
Solid tumors and metastasis rely on angiogenesis for sufficient supply as they grow, making antiangiogenic treatment a promising option in the combat of cancer. Testing of inhalants on the chorio-a...
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- 2021
30. The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids
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Franz Bracher, Nicole Urban, Franz Geisslinger, Karl Sauvageot-Witzku, Karin Bartel, Marco Keller, and Michael Schaefer
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antiproliferative activity ,Carbamate ,Stereochemistry ,medicine.medical_treatment ,Science ,Total synthesis ,ion channels ,Organic chemistry ,Tumor cells ,Ring (chemistry) ,alkaloids ,acyl pictet–spengler reaction ,benzyltetrahydroisoquinolines ,chemistry.chemical_compound ,Residue (chemistry) ,QD241-441 ,chemistry ,protective group ,Group (periodic table) ,medicine ,Methyllithium ,Phenols ,total synthesis - Abstract
We present a systematic investigation on an improved variant of the N-acyl-Pictet–Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N–H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure–activity relationships in this chemotype.
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- 2021
31. Abstracts
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Lucia C. Pérez-Herrera, Maximilian Schaefer, Yury Zhernov, Kateryna Hodiatska, Carsten Bindslev-Jensen, Aleksandr Shcherbakov, Andrei Babenka, Nirmin Juber, Athila Santos, Kevin Sheng-Kai Ma, Sinisa Savic, Olha Shvaratska, Alicia Gallardo Higueras, Salma Abdelhady, and Sergio Moreno
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Chemistry ,Enzymatic hydrolysis ,Immunology ,Camel milk ,Immunology and Allergy ,Food science - Published
- 2021
32. Are the N ‐demethylated metabolites of U‐47700 more active than their parent compound? In vitro μ‐opioid receptor activation of N ‐desmethyl‐U‐47700 and N , N ‐bisdesmethyl‐U‐47700
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Markus R. Meyer, Christophe P. Stove, Frederike Nordmeier, Nadine Schaefer, Annelies Cannaert, and Peter H. Schmidt
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medicine.drug_class ,Chemistry ,Stereochemistry ,Metabolite ,Pharmaceutical Science ,Desmethyl ,In vitro ,Analytical Chemistry ,chemistry.chemical_compound ,Opioid receptor ,U-47700 ,medicine ,Environmental Chemistry ,Potency ,Receptor ,Spectroscopy ,medicine.drug ,EC50 - Abstract
Studies on the tissue distribution of the New Synthetic Opioid U-47700 and its main metabolite N-desmethyl-U-47700 revealed about 6-fold higher metabolite concentrations in pig brain as compared to the parent compound. To better assess the toxic potential of this drug, the aim of this study was to assess the in vitro μ-opioid receptor (MOR) activation potential of the main metabolites of U-47700, N-desmethyl-U-47700 and N,N-bisdesmethyl-U-47700, using a live cell-based reporter assay based on NanoLuc Binary Technology®. Cells stably expressing human MOR and β-arrestin 2 (βarr2), each fused via a flexible linker to two complementary inactive subunits of the nanoluciferase, were seeded on poly-D-lysine-coated 96-well plates and treated with N-desmethyl-U-47700, N,N-bisdesmethyl-U-47700, U-47700, or hydromorphone as reference standard. MOR activation results in functional complementation of the nanoluciferase, which can be assessed via luminescence monitoring. The potency of the metabolites is lower than that of U-47700 (EC50 of 186 nM for U-47700, to 3770 nM for N-desmethyl-U-47700 and >5 μM for N,N-bisdesmethyl-U-47700). The maximal efficacy (Emax ) observed (relative to hydromorphone, set arbitrarily at 100%) decreased from 183% to 127% and 39.2% for U-47700, N-desmethyl-U-47700 and N,N-bisdesmethyl-U-47700, respectively. Thus, the loss of one or two methyl groups reduced the MOR activation potential, which was more pronounced if both methyl groups were removed. It is thus anticipated that the impact on MOR exerted by the higher metabolite concentration in brain has only little - if any - relevance for the strong toxic effects of U-47700.
- Published
- 2021
33. Contrasting the Mechanism of H 2 Activation by Monomeric and Potassium‐Stabilized Dimeric Al I Complexes: Do Potassium Atoms Exert any Cooperative Effect?
- Author
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Alejandro Toro-Labbé, Henry F. Schaefer, and Nery Villegas-Escobar
- Subjects
Reaction mechanism ,Ligand ,Dimer ,Organic Chemistry ,General Chemistry ,Oxidative addition ,Catalysis ,Transition state ,chemistry.chemical_compound ,Crystallography ,Main group element ,chemistry ,Molecule ,Carbenoid - Abstract
Aluminyl anions are low-valent, anionic, and carbenoid aluminum species commonly found stabilized with potassium cations from the reaction of Al-halogen precursors and alkali compounds. These systems are very reactive toward the activation of σ-bonds and in reactions with electrophiles. Various research groups have detected that the potassium atoms play a stabilization role via electrostatic and cation ⋯ π interactions with nearby (aromatic)-carbocyclic rings from both the ligand and from the reaction with unsaturated substrates. Since stabilizing K⋯H bonds are witnessed in the activation of this class of molecules, we aim to unveil the role of these metals in the activation of the smaller and less polarizable H2 molecule, together with a comprehensive characterization of the reaction mechanism. In this work, the activation of H2 utilizing a NON-xanthene-Al dimer, [K{Al(NON)}]2 (D) and monomeric, [Al(NON)]- (M) complexes are studied using density functional theory and high-level coupled-cluster theory to reveal the potential role of K+ atoms during the activation of this gas. Furthermore, we aim to reveal whether D is more reactive than M (or vice versa), or if complicity between the two monomer units exits within the D complex toward the activation of H2 . The results suggest that activation energies using the dimeric and monomeric complexes were found to be very close (around 33 kcal mol-1 ). However, a partition of activation energies unveiled that the nature of the energy barriers for the monomeric and dimeric complexes are inherently different. The former is dominated by a more substantial distortion of the reactants (and increased interaction energies between them). Interestingly, during the oxidative addition, the distortion of the Al complex is minimal, while H2 distorts the most, usually over 0.77 Δ E d i s t ≠ . Overall, it is found here that electrostatic and induction energies between the complexes and H2 are the main stabilizing components up to the respective transition states. The results suggest that the K+ atoms act as stabilizers of the dimeric structure, and their cooperative role on the reaction mechanism may be negligible, acting as mere spectators in the activation of H2 . Cooperation between the two monomers in D is lacking, and therefore the subsequent activation of H2 is wholly disengaged.
- Published
- 2021
34. Delayed and variable late Archaean atmospheric oxidation due to high collision rates on Earth
- Author
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David Nesvorny, C. Koeberl, Laura Schaefer, Toni Schulz, Simone Marchi, William F. Bottke, Timothy W. Lyons, and N. Drabon
- Subjects
geography ,geography.geographical_feature_category ,Earth science ,Archean ,chemistry.chemical_element ,Early Earth ,Oxygen ,Sink (geography) ,Atmosphere ,Flux (metallurgy) ,chemistry ,Extraterrestrial life ,Atmospheric chemistry ,General Earth and Planetary Sciences - Abstract
Frequent violent collisions of impactors from space punctuated the geological and atmospheric evolution of early Earth. It is generally accepted that the most massive collisions altered the chemistry of Earth’s earliest atmosphere, but the consequences of Archaean collisions for atmospheric oxidation are little understood. Early Archaean (4.0–3.5 billion years ago (Ga)) impact flux models are tightly constrained by lunar cratering and radiometric data. Further, a record of the late Archaean (3.5–2.5 Ga) impact flux is provided by terrestrial impact spherule layers—formed by collisions with bodies ≥10–20 km in diameter—although this record is probably incomplete and significant uncertainties remain. Here we show, on the basis of an assessment of impactor-related spherule records and modelling of the atmospheric effects of these impacts, that current bombardment models underestimate the number of late Archaean spherule layers. These findings suggest that the late Archaean impactor flux was up to a factor of ten higher than previously thought. We find that the delivered impactor mass was an important sink of oxygen, suggesting that early bombardment could have delayed Earth’s atmosphere oxidation. In addition, late Archaean large impacts (≥10 km) probably caused drastic oscillations of atmospheric oxygen, with an average time between consecutive collisions of about 15 Myr. This pattern is consistent with a known episode of atmospheric oxygen oscillation at ~2.5 Ga that is bracketed by large impacts recorded by Bee Gorge (~2.54 Ga) and Dales Gorge (~2.49 Ga) spherule layers. The oxygenation of Earth may have been delayed due to high late Archaean extraterrestrial impact rates, which acted as a fluctuating sink of atmospheric oxygen, according to a reassessment of past impactor fluxes and atmospheric chemistry modelling.
- Published
- 2021
35. Hybrid Flow-Batch Model for the Efficient Synthesis of 2-(Dimethylamino)-6-methylpyridin-4-ol
- Author
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Antonio Navarro, Brian A. Schaefer, J. Craig Ruble, Juan A. Rincón, María Luz de la Puente, María Jesús Trigo, María José Nieves-Remacha, and José Eugenio de Diego
- Subjects
Flow (mathematics) ,Chemical engineering ,Chemistry ,Organic Chemistry ,Physical and Theoretical Chemistry - Published
- 2021
36. Nicotine metabolism and its association with CYP2A6 genotype among Indigenous people in Alaska who smoke
- Author
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Jaedon P Avey, Timothy A. Thornton, Laura M. Shireman, Julie A. Beans, Kenneth E. Thummel, Renee Robinson, Rachel F. Tyndale, Krista R. Schaefer, Katrina G. Claw, Denise A. Dillard, and Michael R. Todd
- Subjects
Adult ,Male ,Nicotine ,Genotype ,Population ,Physiology ,RM1-950 ,Urine ,Biology ,030226 pharmacology & pharmacy ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cytochrome P-450 CYP2A6 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetic variation ,medicine ,Humans ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Allele ,Indigenous Peoples ,CYP2A6 ,education ,education.field_of_study ,Research ,General Neuroscience ,Articles ,General Medicine ,Middle Aged ,3. Good health ,chemistry ,Female ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,Cotinine ,Alaska ,medicine.drug - Abstract
Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3′‐hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non‐ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype‐inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E‐08 and 4.08E‐13, respectively). Plasma NMR was also associated with duration of smoking (p value
- Published
- 2021
37. Carbene‐Stabilized Dithiolene (L 0 ) Zwitterions
- Author
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Yuzhong Wang, Phuong M. Tran, Yaoming Xie, Pingrong Wei, John N. Glushka, Henry F. Schaefer, and Gregory H. Robinson
- Subjects
chemistry.chemical_classification ,Dimer ,Silylene ,General Medicine ,General Chemistry ,Catalysis ,chemistry.chemical_compound ,chemistry ,Cleave ,Polymer chemistry ,Theoretical methods ,Imidazole ,Lewis acids and bases ,Carbene ,Alkyl - Abstract
A series of reactions between Lewis bases and an imidazole-based dithione dimer (1) has been investigated. Both cyclic(alkyl)(amino)carbene (CAAC) (2) and N-heterocyclic carbene (NHC) (4), in addition to N-heterocyclic silylene (NHSi) (6), demonstrate the capability to cleave the sulphur-sulphur bonds in 1, giving carbene-stabilized dithiolene (L0 ) zwitterions (3 and 5) and a spirocyclic silicon-dithiolene compound (7), respectively. The bonding nature of 3, 5, and 7 are probed by both experimental and theoretical methods.
- Published
- 2021
38. The three-spin intermediate at the O–O cleavage and proton-pumping junction in heme–Cu oxidases
- Author
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Ziqiao Ding, Antonio C. Roveda, Edward I. Solomon, Andrew W. Schaefer, Sylvia K. Choi, Wesley J. Transue, Anex Jose, and Robert B. Gennis
- Subjects
Hemeproteins ,Multidisciplinary ,Proton ,Cellular respiration ,Escherichia coli Proteins ,Proton Pumps ,Cytochrome b Group ,Photochemistry ,Cleavage (embryo) ,Article ,Electron Transport Complex IV ,Coupling (electronics) ,chemistry.chemical_compound ,chemistry ,Catalytic Domain ,Molecular oxygen ,Oxidoreductases ,Spin (physics) ,Adenosine triphosphate ,Heme ,Copper - Abstract
Breaking down oxygen Molecular oxygen (O 2 ) is the terminal oxidant for respiration in mitochondria and many bacteria. Within membrane-bound heme–copper oxidases, a controlled, four-electron reduction of O 2 to water is coupled to pumping of protons across the membrane that can be used, among other outcomes, to generate adenosine triphosphate. Studying cytochrome bo 3 ubiquinol oxidase, Jose et al . investigated the key P M intermediate, which forms after O–O bond cleavage and precedes proton pumping, using magnetic circular dichroism spectroscopy. The authors observed features demonstrating that P M is a three-spin system, which is consistent with a consensus model including an iron(IV)-oxo species, copper(II) ion, and tyrosyl radical. These results provide an important validation of the O–O cleavage mechanism and open the door to understanding the proton pumping step. —MAF
- Published
- 2021
39. On-Line Composition Analysis of Complex Hydrocarbon Streams by Time-Resolved Fourier Transform Infrared Spectroscopy and Ion–Molecule Reaction Mass Spectrometry
- Author
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Per-Anders Carlsson, Christopher Sauer, Andreas Schaefer, and Anders Lorén
- Subjects
Chemistry ,Analytical chemistry ,Heterogeneous catalysis ,Mass spectrometry ,Chemical reaction ,Toluene ,Article ,Hydrocarbons ,Mass Spectrometry ,Analytical Chemistry ,Hydrocarbon mixtures ,chemistry.chemical_compound ,Spectroscopy, Fourier Transform Infrared ,Fourier transform infrared spectroscopy ,Benzene ,Isomerization - Abstract
On-line composition analysis of complex hydrocarbon mixtures is highly desirable to determine the composition of process streams and to study chemical reactions in heterogeneous catalysis. Here, we show how the combination of time-resolved Fourier transform infrared spectroscopy and ion-molecule-reaction mass spectrometry (IMR-MS) can be used for compositional analysis of processed plant biomass streams. The method is based on the biomass-derived model compound 2,5-dimethylfuran and its potential catalytic conversion to valuable green aromatics, for example, benzene, toluene, and xylenes (BTX) over zeolite β. Numerous conversion products can be determined and quantified simultaneously in a temporal resolution of 4 min-1 without separation of individual compounds. The realization of this method enables us to study activity, selectivity, and changes in composition under transient reaction conditions. For example, increasing isomerization of 2,5-dimethylfuran to 2,4-dimethylfuran, 2-methyl-2-cyclopenten-1-one, and 2-methyl-2-cyclopenten-1-one is observed as the catalyst is exposed to the reactant, while BTX and olefin formation is decreasing.
- Published
- 2021
40. L’association entre protoxyde d’azote et durée de séjour en salle de réveil : une étude observationnelle rétrospective
- Author
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Eswar Sundar, Michael Blank, Salameh Sameh Obeidat, Peter Santer, Karuna Wongtangman, Maximilian Hammer, Maximilian S. Schaefer, Matthias Eikermann, and Luca J Wachtendorf
- Subjects
medicine.medical_specialty ,Postanesthesia care ,biology ,business.industry ,medicine.drug_class ,Medizin ,Retrospective cohort study ,General Medicine ,Nitrous oxide ,equipment and supplies ,biology.organism_classification ,Confidence interval ,Pacu ,chemistry.chemical_compound ,Anesthesiology and Pain Medicine ,chemistry ,Anesthesia ,Anesthesiology ,Medicine ,Antiemetic ,In patient ,business - Abstract
To assess whether intraoperative use of nitrous oxide (N2O) as an adjunct to general anesthesia is associated with a shorter length of stay in the postanesthesia care unit (PACU). We analyzed data from adult patients who underwent non-cardiothoracic surgery under general anesthesia between May 2008 and December 2018. We assessed the association between intraoperative low- and high-dose N2O and PACU length of stay. A total of 148,284 patients were included in the primary analysis. After adjusting for a priori defined confounders, a high dose of N2O significantly decreased PACU length of stay, with a calculated difference of −9.1 min (95% confidence interval [CI], −10.5 to −7.7; P 30 min difference) in patients who underwent complex surgical procedures and received intraoperative antiemetic therapy.
- Published
- 2021
41. Lantern‐Type Divanadium Complexes with Bridging Ligands: Short Metal−Metal Bonds with High Multiple Bond Orders
- Author
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Henry F. Schaefer, Richard H. Duncan Lyngdoh, Derek R. Langstieh, and R. Bruce King
- Subjects
Denticity ,Materials science ,Spin states ,Triple bond ,Quadruple bond ,Bond order ,Atomic and Molecular Physics, and Optics ,Bond length ,Tetragonal crystal system ,chemistry.chemical_compound ,Crystallography ,chemistry ,Carboxylate ,Physical and Theoretical Chemistry - Abstract
Vanadium forms binuclear complexes with a variety of ligands often containing V≡V triple bonds. Many tetragonal divanadium paddlewheel complexes with bridging bidentate ligands have been experimentally characterized. This research exhaustively treats model tetragonal, trigonal, and digonal paddlewheel-type divanadium complexes V2 Lx (L=formamidinate, guanidinate, and carboxylate; x=2, 3, 4), each in the three lowest-energy spin states. The V-V formal bond orders are obtained from metal-metal MO diagrams for representative structures. A number of short V-V multiple bonds of order 3, 3.5, and 4 are found in these model complexes. The short V≡V triple bonds and singlet ground state predicted here for the model tetragonal complexes correspond well with the limited experimental results for the series of known tetragonal paddlewheels. Digonal divanadium lanterns with very short V-V quadruple bonds are predicted as interesting synthetic targets. The V-V bond distances are categorized into distinct ranges according to the formal bond order values from 0.5 to 4. These bond length ranges are compared with the ranges compiled for other divanadium complexes including carbonyl complexes.
- Published
- 2021
42. T- and pH-Dependent Kinetics of the Reactions of ·OH(aq) with Glutaric and Adipic Acid for Atmospheric Aqueous-Phase Chemistry
- Author
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Thomas Schaefer, Xiaomin Sun, Hartmut Herrmann, Yimu Zhang, Oscar N. Ventura, Lin He, and Liang Wen
- Subjects
Atmospheric Science ,chemistry.chemical_compound ,Adipic acid ,Space and Planetary Science ,Geochemistry and Petrology ,Chemistry ,Kinetics ,Aqueous two-phase system ,Ph dependent ,Nuclear chemistry - Published
- 2021
43. Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts
- Author
-
Sze-How Bong, Hartmut Schaefer, Torben Kimhofer, Rubén Gil-Redondo, Maider Bizkarguenaga, Oscar Millet, Philipp Nitschke, Jeremy K. Nicholson, Chiara Bruzzone, Julien Wist, José M. Mato, Reika Masuda, Elaine Holmes, Nieves Embade, Drew Hall, Manfred Spraul, Samantha Lodge, and Ruey Leng Loo
- Subjects
Plasma lipoprotein ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,business.industry ,Lipoproteins ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Metabolite ,Australia ,COVID-19 ,Physiology ,General Chemistry ,Biochemistry ,In vitro diagnostic ,chemistry.chemical_compound ,chemistry ,Fibrinolysis ,Cohort ,Humans ,Medicine ,business ,Biomarkers ,Lipoprotein - Abstract
Quantitative plasma lipoprotein and metabolite profiles were measured on an autonomous community of the Basque Country (Spain) cohort consisting of hospitalized COVID-19 patients (n = 72) and a matched control group (n = 75) and a Western Australian (WA) cohort consisting of (n = 17) SARS-CoV-2 positives and (n = 20) healthy controls using 600 MHz 1H nuclear magnetic resonance (NMR) spectroscopy. Spanish samples were measured in two laboratories using one-dimensional (1D) solvent-suppressed and T2-filtered methods with in vitro diagnostic quantification of lipoproteins and metabolites. SARS-CoV-2 positive patients and healthy controls from both populations were modeled and cross-projected to estimate the biological similarities and validate biomarkers. Using the top 15 most discriminatory variables enabled construction of a cross-predictive model with 100% sensitivity and specificity (within populations) and 100% sensitivity and 82% specificity (between populations). Minor differences were observed between the control metabolic variables in the two cohorts, but the lipoproteins were virtually indistinguishable. We observed highly significant infection-related reductions in high-density lipoprotein (HDL) subfraction 4 phospholipids, apolipoproteins A1 and A2,that have previously been associated with negative regulation of blood coagulation and fibrinolysis. The Spanish and Australian diagnostic SARS-CoV-2 biomarkers were mathematically and biologically equivalent, demonstrating that NMR-based technologies are suitable for the study of the comparative pathology of COVID-19 via plasma phenotyping.
- Published
- 2021
44. Synthesis of Methanesulfonic Acid Directly from Methane: The Cation Mechanism or the Radical Mechanism?
- Author
-
Yucheng Hu, Henry F. Schaefer, Huidong Li, Longfei Li, and Yaoming Xie
- Subjects
chemistry.chemical_compound ,chemistry ,Cationic polymerization ,General Materials Science ,Protonation ,Electrolyte ,Physical and Theoretical Chemistry ,Photochemistry ,Methanesulfonic acid ,Chain reaction ,Mechanism (sociology) ,Oleum ,Methane - Abstract
In 2019, Diaz-Urrutia and Ott developed a high-yield method for direct conversion of methane to methanesulfonic acid and proposed a cationic chain reaction mechanism. However, Roytman and Singleton questioned this mechanism, and they favored a free-radical mechanism. In the present paper, we studied both the cationic chain and radical mechanisms and found the radical mechanism is more favorable, since it has a much lower energy barrier. However, the radical mechanism has not considered the effect of ions for the reaction taking place in oleum. Thus, we studied a simple model of a protonated radical mechanism, which further lowers the energy barrier. Although the true mechanism for the CH4 + SO3 reaction could be more complicated in electrolyte solutions, this model should be helpful for the further study of the mechanism of this reaction.
- Published
- 2021
45. Carbonylic-Carbon-Centered Mechanism for Catalytic α-Methylation
- Author
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Henry F. Schaefer, Longfei Li, Zeyu Wu, Yaoming Xie, Wan Li, and Xuena Lu
- Subjects
Inorganic Chemistry ,chemistry ,Organic Chemistry ,chemistry.chemical_element ,Methylation ,Physical and Theoretical Chemistry ,Carbon ,Combinatorial chemistry ,Mechanism (sociology) ,Catalysis - Published
- 2021
46. An exploratory analysis of the competing effects of alcohol use and advanced hepatic fibrosis on serum HDL
- Author
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Augustin G. L. Vannier, Amanda PeBenito, Raymond T. Chung, Esperance A. Schaefer, Jay Luther, Vladislav G Fomin, and Russell P. Goodman
- Subjects
Liver Cirrhosis ,medicine.medical_specialty ,Alcohol Drinking ,Alcohol ,Negative association ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Liver disease ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Hematology ,business.industry ,General Medicine ,Exploratory analysis ,medicine.disease ,Cross-Sectional Studies ,chemistry ,Baseline characteristics ,030211 gastroenterology & hepatology ,business ,Hepatic fibrosis - Abstract
While alcohol use has been shown to increase serum HDL, advanced liver disease associates with decreased serum HDL. The combined influence of alcohol consumption and liver fibrosis is poorly defined. In this study, we sought to investigate the competing effects of alcohol use and hepatic fibrosis on serum HDL and to determine if the presence of advanced hepatic fibrosis ablates the reported effect of alcohol consumption on serum HDL. We performed a cross-sectional, exploratory analysis examining the interaction between alcohol use and advanced hepatic fibrosis on serum HDL levels in 10,528 patients from the Partners Biobank. Hepatic fibrosis was assessed using the FIB-4 index. We excluded patients with baseline characteristics that affect serum HDL, independent of alcohol use or the presence or advanced hepatic fibrosis. We observed an incremental correlation between increasing HDL levels and amount of alcohol consumed (P Pvalue: 0.0001). Finally, when comparing subjects with advanced hepatic fibrosis who do not use alcohol to those who do, we observed that alcohol use is associated with increased HDL levels (54.58 mg/dL vs 67.26 mg/dL,p = 0.0009). This HDL-elevating effect of alcohol was more pronounced than that seen in patients without evidence of advanced hepatic fibrosis (60.88 mg/dL vs 67.93 mg/dL,p
- Published
- 2021
47. Extracellular Matrix Remodeling in Chronic Liver Disease
- Author
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Cristina Ortiz, Xavier Trepat, Robert Schierwagen, Liliana Schaefer, Jonel Trebicka, and Sabine Klein
- Subjects
0301 basic medicine ,Cell ,Liver fibrosis ,Matrix metalloproteinase ,Matrix (biology) ,Chronic liver disease ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,TGF-β1 ,medicine ,Hepatic stellate cell ,Chemistry ,General Medicine ,medicine.disease ,Metalloproteinases ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Chronic Liver Disease (MF Lobato, Section Editor) ,Collagen ,Hepatic fibrosis ,Myofibroblast - Abstract
Purpose of the Review This review aims to summarize the current knowledge of the extracellular matrix remodeling during hepatic fibrosis. We discuss the diverse interactions of the extracellular matrix with hepatic cells and the surrounding matrix in liver fibrosis, with the focus on the molecular pathways and the mechanisms that regulate extracellular matrix remodeling. Recent Findings The extracellular matrix not only provides structure and support for the cells, but also controls cell behavior by providing adhesion signals and by acting as a reservoir of growth factors and cytokines. Summary Hepatic fibrosis is characterized by an excessive accumulation of extracellular matrix. During fibrogenesis, the natural remodeling process of the extracellular matrix varies, resulting in the excessive accumulation of its components, mainly collagens. Signals released by the extracellular matrix induce the activation of hepatic stellate cells, which are the major source of extracellular matrix and most abundant myofibroblasts in the liver. Graphical abstract
- Published
- 2021
48. Carbon Incorporation in MOCVD of MoS2 Thin Films Grown from an Organosulfide Precursor
- Author
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Clément Hébert, José Santiso, Elena del Corro, Christian M. Schaefer, José Manuel Caicedo Roque, Justin R. Sperling, Jose A. Garrido, Amador Pérez-Tomás, Jessica Bousquet, Guillaume Sauthier, European Commission, Generalitat de Catalunya, and Universidad Autónoma de Barcelona
- Subjects
Chemical vapour deposition ,X-ray photoelectron spectroscopy ,Chemical compositions ,Materials science ,Thin films ,General Chemical Engineering ,chemistry.chemical_element ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Transition metal dichalcogenides ,Molybdenum hexacarbonyl ,Effect of temperature ,A3. metal organic chemical vapor deposition (MOCVD) ,Materials Chemistry ,Metalorganic vapour phase epitaxy ,Thin film ,Two Dimensional (2 D) ,Nanographitic carbons ,Precursors ,General Chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Chemical engineering ,chemistry ,0210 nano-technology ,Electronic application ,Carbon ,Pyrolysis - Abstract
With the rise of two-dimensional (2D) transition-metal dichalcogenide (TMD) semiconductors and their prospective use in commercial (opto)electronic applications, it has become key to develop scalable and reliable TMD synthesis methods with well-monitored and controlled levels of impurities. While metal-organic chemical vapor deposition (MOCVD) has emerged as the method of choice for large-scale TMD fabrication, carbon (C) incorporation arising during MOCVD growth of TMDs has been a persistent concern-especially in instances where organic chalcogen precursors are desired as a less hazardous alternative to more toxic chalcogen hydrides. However, the underlying mechanisms of such unintentional C incorporation and the effects on film growth and properties are still elusive. Here, we report on the role of C-containing side products of organosulfur precursor pyrolysis in MoS2 thin films grown from molybdenum hexacarbonyl Mo(CO)6 and diethyl sulfide (CH3CH2)2S (DES). By combining in situ gas-phase monitoring with ex situ microscopy and spectroscopy analyses, we systematically investigate the effect of temperature and Mo(CO)6/DES/H2 gas mixture ratios on film morphology, chemical composition, and stoichiometry. Aiming at high-quality TMD growth that typically requires elevated growth temperatures and high DES/Mo(CO)6 precursor ratios, we observed that temperatures above DES pyrolysis onset (â 600 °C) and excessive DES flow result in the formation of nanographitic carbon, competing with MoS2 growth. We found that by introducing H2 gas to the process, DES pyrolysis is significantly hindered, which reduces carbon incorporation. The C content in the MoS2 films is shown to quench the MoS2 photoluminescence and influence the trion-To-exciton ratio via charge transfer. This finding is fundamental for understanding process-induced C impurity doping in MOCVD-grown 2D semiconductors and might have important implications for the functionality and performance of (opto)electronic devices., This work was funded by the European Union’s Horizon 2020 research and innovation programme (BrainCom, grant no. 732032, Nanosmart, grant no. 825430 and Graphene Flagship Core 3, grant no. 881603). We also acknowledge funding from Generalitat de Catalunya (2017 SGR 1426), and the 2DTecBio (FIS2017-85787-R) funded by the Spanish Ministry of Science, Innovation and Universities, the Spanish Research Agency (AEI), and the European Regional Development Fund (FEDER/UE). The ICN2 is funded by the CERCA programme/Generalitat de Catalunya and supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706). C.M.S. acknowledges that this work has been done within the framework of the Ph.D. program in Materials Science of the Autonomous University of Barcelona. Furthermore, C.M.S. wants to thank Anh Tuan Hoang for fruitful discussions.
- Published
- 2021
49. Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome
- Author
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Sven Pettersson, Ruey Leng Loo, Monique Ryan, Manfred Spraul, Sze-How Bong, Dale W. Edgar, Philipp Nitschke, Rongchang Yang, Sofina Begum, Samantha Lodge, Torben Kimhofer, Sung Tong Chin, Nathan G. Lawler, Toby Richards, Reika Masuda, Julien Wist, John C. Lindon, Luke Whiley, Drew Hall, Hartmut Schaefer, Berin A. Boughton, Aude-Claire Morillon, Bu B. Yeap, Elaine Holmes, Nicola Gray, and Jeremy K. Nicholson
- Subjects
0301 basic medicine ,myalgia ,Magnetic Resonance Spectroscopy ,multiorgan disease ,Biochemistry ,Gastroenterology ,TOXICITY ,SERUM ,TAURINE ,chemistry.chemical_compound ,phenoconversion ,Respiratory system ,Neopterin ,PROTON NMR-SPECTROSCOPY ,Pathophysiology ,Biomarker (medicine) ,medicine.symptom ,03 Chemical Sciences ,Life Sciences & Biomedicine ,Biochemistry & Molecular Biology ,medicine.medical_specialty ,Lipoproteins ,Anosmia ,SARS-COV-2 INFECTION ,Asymptomatic ,Biochemical Research Methods ,Article ,03 medical and health sciences ,Internal medicine ,REVEALS ,medicine ,Humans ,plasma ,long-COVID syndrome ,amino acids ,Science & Technology ,030102 biochemistry & molecular biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,biomarkers ,General Chemistry ,NEOPTERIN ,06 Biological Sciences ,post-acute COVID-19 syndrome ,phenoreversion ,MODEL ,030104 developmental biology ,chemistry ,business ,Kynurenine - Abstract
We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2 p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.
- Published
- 2021
50. Perimortem Distribution of U-47700, Tramadol and Their Main Metabolites in Pigs Following Intravenous Administration
- Author
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Matthias W. Laschke, Michael D. Menger, Frederike Nordmeier, Markus R. Meyer, Peter H. Schmidt, Adrian A Doerr, Nadja Walle, S. Potente, and Nadine Schaefer
- Subjects
Swine ,Health, Toxicology and Mutagenesis ,Metabolite ,Physiology ,Adipose tissue ,Urine ,Toxicology ,01 natural sciences ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Environmental Chemistry ,Toxicokinetics ,030216 legal & forensic medicine ,Tramadol ,Chemical Health and Safety ,010401 analytical chemistry ,Forensic toxicology ,0104 chemical sciences ,Analgesics, Opioid ,medicine.anatomical_structure ,chemistry ,Benzamides ,Duodenum ,Administration, Intravenous ,Chromatography, Liquid ,Homogenization (biology) ,medicine.drug - Abstract
In spite of a decreasing number of new releases, new synthetic opioids (NSOs) are gaining increasing importance in postmortem (PM) forensic toxicology. For the interpretation of analytical results, toxicokinetic (TK) data, e.g., on tissue distribution, are helpful. Concerning NSOs, such data are usually not available due to the lack of controlled human studies. Hence, a controlled TK study using pigs was carried out, and the tissue distribution of U-47700 and tramadol as reference was examined. Twelve pigs received an intravenous dose of 100 µg/kg body weight (BW) U-47700 or 1,000 µg/kg BW tramadol. Eight hours after administration, the animals were put to death with T61. Relevant organs, body fluids and tissues were sampled. After homogenization and solid-phase extraction, quantification was performed applying standard addition and liquid chromatography--tandem mass spectrometry. At the time of death, the two parent compounds were determined in all analyzed specimens. Regarding U-47700, concentrations were highest in duodenum content, bile fluid and adipose tissue (AT). Concerning tramadol, next to bile fluid and duodenum content, highest concentrations were determined in the lung. Regarding the metabolites, N-desmethyl-U-47700 and O-desmethyltramadol (ODT) were detected in all analyzed specimens except for AT (ODT). Higher metabolite concentrations were found in specimens involved in metabolism. N-desmethyl-U-47700 showed much higher concentrations in routinely analyzed organs (lung, liver and kidney) than U-47700. To conclude, besides the routinely analyzed specimens in PM toxicology such as blood, urine or standard specimens like kidney or liver, AT, bile fluid and duodenum content could serve as alternative matrices. In case of U-47700, quantification of the main metabolite N-desmethyl-U-47700 is highly recommendable.
- Published
- 2021
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