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1579 Publications visible to you, out of a total of 1579
An electron transfer competent structural ensemble of membrane-bound cytochrome P450 1A1 and cytochrome P450 oxidoreductase

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Abstract Cytochrome P450 (CYP) heme monooxygenases require two electrons for their catalytic cycle. For mammalian microsomal CYPs, key enzymes for xenobiotic metabolism and steroidogenesis and important …roidogenesis and important drug targets and biocatalysts, the electrons are transferred by NADPH-cytochrome P450 oxidoreductase (CPR). No structure of a mammalian CYP–CPR complex has been solved experimentally, hindering understanding of the determinants of electron transfer (ET), which is often rate-limiting for CYP reactions. Here, we investigated the interactions between membrane-bound CYP 1A1, an antitumor drug target, and CPR by a multiresolution computational approach. We find that upon binding to CPR, the CYP 1A1 catalytic domain becomes less embedded in the membrane and reorients, indicating that CPR may affect ligand passage to the CYP active site. Despite the constraints imposed by membrane binding, we identify several arrangements of CPR around CYP 1A1 that are compatible with ET. In the complexes, the interactions of the CPR FMN domain with the proximal side of CYP 1A1 are supplemented by more transient interactions of the CPR NADP domain with the distal side of CYP 1A1. Computed ET rates and pathways agree well with available experimental data and suggest why the CYP–CPR ET rates are low compared to those of soluble bacterial CYPs.

Authors: Goutam Mukherjee, Prajwal P. Nandekar, Rebecca C. Wade

Date Published: 1st Dec 2021

Publication Type: Journal

Use of a quantitative data report in a hypothetical decision scenario for health policymaking: a computer-assisted laboratory study

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Background: Quantitative data reports are widely produced to inform health policy decisions. Policymakers are expected to critically assess provided information in order to incorporate the best available … evidence into the decision-making process. Many other factors are known to influence this process, but little is known about how quantitative data reports are actually read. We explored the reading behavior of (future) health policy decision-makers, using innovative methods. Methods: We conducted a computer-assisted laboratory study, involving starting and advanced students in medicine and health sciences, and professionals as participants. They read a quantitative data report to inform a decision on the use of resources for long-term care in dementia in a hypothetical decision scenario. Data were collected through eye-tracking, questionnaires, and a brief interview. Eye-tracking data were used to generate ‘heatmaps’ and five measures of reading behavior. The questionnaires provided participants’ perceptions of understandability and helpfulness as well as individual characteristics. Interviews documented reasons for attention to specific report sections. The quantitative analysis was largely descriptive, complemented by Pearson correlations. Interviews were analyzed by qualitative content analysis. Results: In total, 46 individuals participated [students (85%), professionals (15%)]. Eye-tracking observations showed that the participants spent equal time and attention for most parts of the presented report, but were less focused when reading the methods section. The qualitative content analysis identified 29 reasons for attention to a report section related to four topics. Eye-tracking measures were largely unrelated to participants’ perceptions of understandability and helpfulness of the report. Conclusions: Eye-tracking data added information on reading behaviors that were not captured by questionnaires or interviews with health decision-makers.

Authors: Pamela Wronski, Michel Wensing, Sucheta Ghosh, Lukas Gärttner, Wolfgang Müller, Jan Koetsenruijter

Date Published: 1st Dec 2021

Publication Type: Journal

Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

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Abstract Rare variants in the beta-glucocerebrosidase gene ( GBA1 ) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease …hich often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Authors: Muhammad Aslam, Nirosiya Kandasamy, Anwar Ullah, Nagarajan Paramasivam, Mehmet Ali Öztürk, Saima Naureen, Abida Arshad, Mazhar Badshah, Kafaitullah Khan, Muhammad Wajid, Rashda Abbasi, Muhammad Ilyas, Roland Eils, Matthias Schlesner, Rebecca C. Wade, Nafees Ahmad, Jakob von Engelhardt

Date Published: 1st Dec 2021

Publication Type: Journal

Weighing stars from birth to death: mass determination methods across the HRD

Abstract

Not specified

Authors: Aldo Serenelli, Achim Weiss, Conny Aerts, George C. Angelou, David Baroch, Nate Bastian, Paul G. Beck, Maria Bergemann, Joachim M. Bestenlehner, Ian Czekala, Nancy Elias-Rosa, Ana Escorza, Vincent Van Eylen, Diane K. Feuillet, Davide Gandolfi, Mark Gieles, Léo Girardi, Yveline Lebreton, Nicolas Lodieu, Marie Martig, Marcelo M. Miller Bertolami, Joey S. G. Mombarg, Juan Carlos Morales, Andrés Moya, Benard Nsamba, Krešimir Pavlovski, May G. Pedersen, Ignasi Ribas, Fabian R. N. Schneider, Victor Silva Aguirre, Keivan G. Stassun, Eline Tolstoy, Pier-Emmanuel Tremblay, Konstanze Zwintz

Date Published: 1st Dec 2021

Publication Type: Journal

Metallicity-dependent nucleosynthetic yields of Type Ia supernovae originating from double detonations of sub- M Ch white dwarfs

Abstract

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Authors: Sabrina Gronow, Benoit Côté, Florian Lach, Ivo R. Seitenzahl, Christine E. Collins, Stuart A. Sim, Friedrich K. Röpke

Date Published: 1st Dec 2021

Publication Type: Journal

Vorhersagen sind schwer, vor allem die Zukunft betreffend: Kurzzeitprognosen in der Pandemie

Abstract

Not specified

Authors: Johannes Bracher, Daniel Wolffram, Tilmann Gneiting, Melanie Schienle

Date Published: 1st Dec 2021

Publication Type: Journal

The sum of Lagrange numbers

Abstract

Not specified

Authors: Jonah Gaster, Brice Loustau

Date Published: 1st Dec 2021

Publication Type: Journal

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