27 results on '"Bensberg M"'
Search Results
2. Health promotion - who, us? Developing health promoting emergency departments
- Author
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Kennedy, M and Bensberg, M
- Published
- 2001
3. The New Public Health: 2nd edition (2002)
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Bensberg, M., primary
- Published
- 2003
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4. A framework for health promoting emergency departments
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Bensberg, M., primary
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- 2002
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5. Identifying the opportunities for health promoting emergency departments
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Bensberg, M
- Published
- 2003
6. Heron: Visualizing and Controlling Chemical Reaction Explorations and Networks.
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Müller CH, Steiner M, Unsleber JP, Weymuth T, Bensberg M, Csizi KS, Mörchen M, Türtscher PL, and Reiher M
- Abstract
Automated and high-throughput quantum chemical investigations into chemical processes have become feasible in great detail and broad scope. This results in an increase in complexity of the tasks and in the amount of generated data. An efficient and intuitive way for an operator to interact with these data and to steer virtual experiments is required. Here, we introduce Heron, a graphical user interface that allows for advanced human-machine interactions with quantum chemical exploration campaigns into molecular structure and reactivity. Heron offers access to interactive and automated explorations of chemical reactions with standard electronic structure modules, haptic force feedback, microkinetic modeling, and refinement of data by automated correlated calculations including black-box complete active space calculations. It is tailored to the exploration and analysis of vast chemical reaction networks. We show how interoperable modules enable advanced workflows and pave the way for routine low-entrance-barrier access to advanced modeling techniques.
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- 2024
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7. SCINE-Software for chemical interaction networks.
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Weymuth T, Unsleber JP, Türtscher PL, Steiner M, Sobez JG, Müller CH, Mörchen M, Klasovita V, Grimmel SA, Eckhoff M, Csizi KS, Bosia F, Bensberg M, and Reiher M
- Abstract
The software for chemical interaction networks (SCINE) project aims at pushing the frontier of quantum chemical calculations on molecular structures to a new level. While calculations on individual structures as well as on simple relations between them have become routine in chemistry, new developments have pushed the frontier in the field to high-throughput calculations. Chemical relations may be created by a search for specific molecular properties in a molecular design attempt, or they can be defined by a set of elementary reaction steps that form a chemical reaction network. The software modules of SCINE have been designed to facilitate such studies. The features of the modules are (i) general applicability of the applied methodologies ranging from electronic structure (no restriction to specific elements of the periodic table) to microkinetic modeling (with little restrictions on molecularity), full modularity so that SCINE modules can also be applied as stand-alone programs or be exchanged for external software packages that fulfill a similar purpose (to increase options for computational campaigns and to provide alternatives in case of tasks that are hard or impossible to accomplish with certain programs), (ii) high stability and autonomous operations so that control and steering by an operator are as easy as possible, and (iii) easy embedding into complex heterogeneous environments for molecular structures taken individually or in the context of a reaction network. A graphical user interface unites all modules and ensures interoperability. All components of the software have been made available as open source and free of charge., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND) license (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
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- 2024
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8. Uncertainty-Aware First-Principles Exploration of Chemical Reaction Networks.
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Bensberg M and Reiher M
- Abstract
Exploring large chemical reaction networks with automated exploration approaches and accurate quantum chemical methods can require prohibitively large computational resources. Here, we present an automated exploration approach that focuses on the kinetically relevant part of the reaction network by interweaving (i) large-scale exploration of chemical reactions, (ii) identification of kinetically relevant parts of the reaction network through microkinetic modeling, (iii) quantification and propagation of uncertainties, and (iv) reaction network refinement. Such an uncertainty-aware exploration of kinetically relevant parts of a reaction network with automated accuracy improvement has not been demonstrated before in a fully quantum mechanical approach. Uncertainties are identified by local or global sensitivity analysis. The network is refined in a rolling fashion during the exploration. Moreover, the uncertainties are considered during kinetically steering of a rolling reaction network exploration. We demonstrate our approach for Eschenmoser-Claisen rearrangement reactions. The sensitivity analysis identifies that only a small number of reactions and compounds are essential for describing the kinetics reliably, resulting in efficient explorations without sacrificing accuracy and without requiring prior knowledge about the chemistry unfolding.
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- 2024
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9. Corresponding Active Orbital Spaces along Chemical Reaction Paths.
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Bensberg M and Reiher M
- Abstract
The accuracy of reaction energy profiles calculated with multiconfigurational electronic structure methods and corrected by multireference perturbation theory depends crucially on consistent active orbital spaces selected along the reaction path. However, it has been challenging to choose molecular orbitals that can be considered corresponding in different molecular structures. Here, we demonstrate how active orbital spaces can be selected consistently along reaction coordinates in a fully automatized way. The approach requires no structure interpolation between reactants and products. Instead, it emerges from a synergy of the Direct Orbital Selection orbital mapping ansatz combined with our fully automated active space selection algorithm autoCAS. We demonstrate our algorithm for the potential energy profile of the homolytic carbon-carbon bond dissociation and rotation around the double bond of 1-pentene in the electronic ground state. However, our algorithm also applies to electronically excited Born-Oppenheimer surfaces.
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- 2023
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10. On the accuracy of orbital based multi-level approaches for closed-shell transition metal chemistry.
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Amanollahi Z, Lampe L, Bensberg M, Neugebauer J, and Feldt M
- Abstract
In this work, we investigate the accuracy of the local molecular orbital molecular orbital (LMOMO) scheme and projection-based wave function-in-density functional theory (WF-in-DFT) embedding for the prediction of reaction energies and barriers of typical reactions involving transition metals. To analyze the dependence of the accuracy on the system partitioning, we apply a manual orbital selection for LMOMO as well as the so-called direct orbital selection (DOS) for both approaches. We benchmark these methods on 30 closed shell reactions involving 16 different transition metals. This allows us to devise guidelines for the manual selection as well as settings for the DOS that provide accurate results within an error of 2 kcal mol
-1 compared to local coupled cluster. To reach this accuracy, on average 55% of the occupied orbitals have to be correlated with coupled cluster for the current test set. Furthermore, we find that LMOMO gives more reliable relative energies for small embedded regions than WF-in-DFT embedding.- Published
- 2023
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11. Orbital pair selection for relative energies in the domain-based local pair natural orbital coupled-cluster method.
- Author
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Bensberg M and Neugebauer J
- Abstract
For the accurate computation of relative energies, domain-based local pair natural orbital coupled-cluster [DLPNO-CCSD(T
0 )] has become increasingly popular. Even though DLPNO-CCSD(T0 ) shows a formally linear scaling of the computational effort with the system size, accurate predictions of relative energies remain costly. Therefore, multi-level approaches are attractive that focus the available computational resources on a minor part of the molecular system, e.g., a reaction center, where changes in the correlation energy are expected to be the largest. We present a pair-selected multi-level DLPNO-CCSD(T0 ) ansatz that automatically partitions the orbital pairs according to their contribution to the overall correlation energy change in a chemical reaction. To this end, the localized orbitals are mapped between structures in the reaction; all pair energies are approximated through computationally efficient semi-canonical second-order Møller-Plesser perturbation theory, and the orbital pairs for which the pair energies change significantly are identified. This multi-level approach is significantly more robust than our previously suggested, orbital selection-based multi-level DLPNO-CCSD(T0 ) ansatz [M. Bensberg and J. Neugebauer, J. Chem. Phys. 155, 224102 (2021)] for reactions showing only small changes in the occupied orbitals. At the same time, it is even more efficient without added input complexity or accuracy loss compared to the full DLPNO-CCSD(T0 ) calculation. We demonstrate the accuracy of the multi-level approach for a total of 128 chemical reactions and potential energy curves of weakly interacting complexes from the S66x8 benchmark set.- Published
- 2022
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12. Solvation Free Energies in Subsystem Density Functional Theory.
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Bensberg M, Türtscher PL, Unsleber JP, Reiher M, and Neugebauer J
- Abstract
For many chemical processes the accurate description of solvent effects are vitally important. Here, we describe a hybrid ansatz for the explicit quantum mechanical description of solute-solvent and solvent-solvent interactions based on subsystem density functional theory and continuum solvation schemes. Since explicit solvent molecules may compromise the scalability of the model and transferability of the predicted solvent effect, we aim to retain both, for different solutes as well as for different solvents. The key for the transferability is the consistent subsystem decomposition of solute and solvent. The key for the scalability is the performance of subsystem DFT for increasing numbers of subsystems. We investigate molecular dynamics and stationary point sampling of solvent configurations and compare the resulting (Gibbs) free energies to experiment and theoretical methods. We can show that with our hybrid model reaction barriers and reaction energies are accurately reproduced compared to experimental data.
- Published
- 2022
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13. Direct orbital selection within the domain-based local pair natural orbital coupled-cluster method.
- Author
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Bensberg M and Neugebauer J
- Abstract
Domain-based local pair natural orbital coupled cluster (DLPNO-CC) has become increasingly popular to calculate relative energies (e.g., reaction energies and reaction barriers). It can be applied within a multi-level DLPNO-CC-in-DLPNO-CC ansatz to reduce the computational cost and focus the available computational resources on a specific subset of the occupied orbitals. We demonstrate how this multi-level DLPNO-CC ansatz can be combined with our direct orbital selection (DOS) approach [M. Bensberg and J. Neugebauer, J. Chem. Phys. 150, 214106 (2019)] to automatically select orbital sets for any multi-level calculation. We find that the parameters for the DOS procedure can be chosen conservatively such that they are transferable between reactions. The resulting automatic multi-level DLPNO-CC method requires no user input and is extremely robust and accurate. The computational cost is easily reduced by a factor of 3 without sacrificing accuracy. We demonstrate the accuracy of the method for a total of 61 reactions containing up to 174 atoms and use it to predict the relative stability of conformers of a Ru-based catalyst.
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- 2021
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14. TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia.
- Author
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Bensberg M, Rundquist O, Selimović A, Lagerwall C, Benson M, Gustafsson M, Vogt H, Lentini A, and Nestor CE
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- Antimetabolites, Antineoplastic pharmacology, Antioxidants pharmacology, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dioxygenases genetics, Dioxygenases metabolism, Drug Therapy, Combination, Humans, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic, RNA-Seq, Tumor Cells, Cultured, Ascorbic Acid pharmacology, Azacitidine pharmacology, Biomarkers, Tumor metabolism, DNA Methylation, DNA-Binding Proteins antagonists & inhibitors, Dioxygenases antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2 -silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2 -silenced T-ALL., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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15. Applying influence for systems change in a large-scale community-based prevention intervention.
- Author
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Bensberg M
- Subjects
- Government, Health Personnel, Humans, Interpersonal Relations, Interviews as Topic, Qualitative Research, Victoria, Health Promotion methods, Public Health methods
- Abstract
Study objectives and importance: The study aimed to explore how a 'self-in-the-system' approach was understood and applied by Healthy Together Community (HTC) practitioners, as part of Healthy Together Victoria's (HTV) systems approach to community-level health promotion. Self-in-the-system tactics were a means of systems practice within HTV, where practitioners viewed their connections to others as parts of the systems that surround them. It enabled them to intervene via exerting influence, by drawing upon relationships to leverage what people can contribute to achieve change. Study type and methods: This qualitative research included 31 primary semistructured interviews. The initial participants were identified using purposive sampling and subsequent participants were nominated via snowball recruitment. The interview questions focused on participants' understanding of systems thinking and about how it had been developed and applied in HTCs. The interviews were recorded and transcribed verbatim. Inductive thematic analysis was based on Braun and Clarke's six-phase analysis framework. Results: The research findings show that some of the HTC practitioners viewed themselves as part of the prevention system and were able to draw upon their relationships to achieve change. They had invested time to develop trusted connections upon which to engage and encourage cooperation. The notion of a 'prevention change agent' developed, referring to practitioners who used their influence to achieve HTC goals. This practical know-how was developing in HTCs as people were able to describe the concept, rather than provide examples of working in this way. Conclusion: Within a systems approach to community-level health promotion, a practitioner's capacity to identify their role in complex adaptive systems and their ability to influence others are potentially powerful skills to facilitate change. Self in the system is a developing skill for systems practice for prevention and it may add more systemic ways of working compared with traditional programmatic methods., Competing Interests: MB was an employee of the DHHS during this research. The views in this paper do not necessarily represent those of the DHHS.
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- 2021
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16. Building a Prevention System: Infrastructure to Strengthen Health Promotion Outcomes.
- Author
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Bensberg M, Joyce A, and Wilson E
- Subjects
- Australia, Delivery of Health Care, Humans, Workforce, Health Promotion, Leadership
- Abstract
Prevention systems improve the performance of health promotion interventions. This research describes the establishment of the Australian state government initiative, Healthy Together Victoria's (HTV) macro infrastructure for the delivery of large-scale prevention interventions., Methods: This paper reports on findings of 31 semi-structured interviews about participants' understanding of systems thinking and their reflections of the strengths and weaknesses of the HTV prevention system. A chronic disease prevention framework informed the coding that was used to create a causal loop diagram and a core feedback loop to illustrate the results., Results: Findings highlighted that HTV created a highly connected prevention system that included a sizeable workforce, significant funding and supportive leadership. Operating guidelines, additional professional development and real-time evaluation were significant gaps, which hindered systems practice. For inexperienced systems thinkers, these limitations encouraged them to implement programs, rather than interact with the seemingly ambiguous systems methods., Conclusions: HTV was an innovative attempt to strengthen health promotion infrastructure, creating a common language and shared understanding of prevention system requirements. However, the model was inadequate for HTV to achieve population-level reductions in chronic disease as system oversight was missing, as was an intervention delivery focus. Clarity was needed to define the systems practice that HTV was seeking to achieve. Importantly, the HTV prevention system needed to be understood as complex and adaptive, and not prioritized as individual parts.
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- 2021
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17. Developing a Systems Mindset in Community-Based Prevention.
- Author
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Bensberg M
- Subjects
- Humans, Qualitative Research, Emotions
- Abstract
Background. A systems mindset is the ability to see problems in their wider context and in terms of their underlying structure. This research describes how a systems mindset was understood and applied by prevention practitioners in a large-scale community-based initiative that employed a systems thinking approach. Method. This qualitative research included 31 primary semistructured interviews. Deductive thematic analysis was based on Braun and Clarke's analysis framework and was guided by Senge and Scharmer's knowledge-creating system. Results. The practitioners had been introduced to systems theory and were aware of complex problems and the need for equally sophisticated solutions. Their knowledge was not in-depth, although this may be adequate, as a theoretical overview seemed to be sufficient to support practice. A range of tools was available to practitioners to guide their systems mindset; however, none were preferred. Practitioners' awareness of the tools varied, as did their feelings toward them as some found them helpful and others did not. A narrower focus on tools could have benefited those who had not yet grasped systems theory. The use of projects within a systems approach confused some practitioners, yet others saw them as platforms to leverage change from. Implications for practice. With a systems mindset practitioners are able to develop systemic solutions to difficult problems. To do this, they require an overview of complex adaptive systems theory, an applied understanding of systems tools, and an experiential learning opportunity to shift their knowledge into practical know-how.
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- 2021
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18. Density functional theory based embedding approaches for transition-metal complexes.
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Bensberg M and Neugebauer J
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Transition metal species are commonly discussed by considering the metal atom embedded in a ligand environment. This apparently makes them interesting targets for modern embedding strategies based on Kohn-Sham density functional theory (DFT), which aim at modelling accurate predictions for large systems by combining different quantum chemical methods. In this perspective, we will focus on subsystem density functional theory and projection-based embedding. We review the developments in the field for transition metal species, demonstrate benefits, drawbacks and analyse error sources of the different strategies using the example of chromium hexacarbonyle, before giving a perspective where the field is currently heading.
- Published
- 2020
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19. Building a systems thinking prevention workforce.
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Bensberg M, Allender S, and Sacks G
- Subjects
- Humans, Leadership, Systems Analysis, Workforce, Capacity Building, Health Promotion
- Abstract
Issue Addressed: Healthy Together Victoria (HTV) was a large-scale intervention that adopted a systems approach to prevention. It established the capability of an inexperienced workforce by cultivating their understanding of systems theories, tools and practice. This paper explores how this capacity was developed and what helped and hindered the process., Methods: This qualitative research included 31 primary semi-structured interviews that focused on participants' understanding of systems thinking. Deductive thematic analysis was undertaken. A workforce development framework informed the coding that was used to create a causal loop diagram., Results: The findings display the multiple influencers on capacity-building. Practice change was enabled with training-although it lacked coordination and participation was limited. Yet, the systems approach was strengthened with governance arrangements, policies, funding, team support and leadership that empowered practitioners to trial systems methods. Capacity-building was hindered by HTV's unspecified theory that made it harder for novice practitioners to grasp. Funding cuts due to political changes reduced the initiative's duration and prompted resignations, causing the newfound experience to exit the workforce., Conclusion: Capacity-building for systems practice requires a holistic approach of simultaneous, complimentary actions that address the individual and environmental influences of workforce development, especially the drivers of organisational culture that facilitate new practice. SO WHAT?: Effective training methods should specifically teach skills and knowledge that help practitioners to implement systems thinking. The workforce development requirements of other contributors also need to be considered, in addition to the policies, opportunities and resources that embed practice change., (© 2020 Australian Health Promotion Association.)
- Published
- 2020
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20. Orbital Alignment for Accurate Projection-Based Embedding Calculations along Reaction Paths.
- Author
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Bensberg M and Neugebauer J
- Abstract
In projection-based embedding (PbE) the subsystem partitioning of a chemical system is based on localized orbitals. We demonstrate how the localization step can lead to inconsistent orbital spaces along reaction paths, with severe consequences for reaction barriers and energies. We propose an orbital alignment procedure that resolves this problem without manual input. The usefulness of this alignment is demonstrated for a reaction benchmark set in combination with a direct orbital selection approach to automatize PbE calculations of double hybrid-in-nonhybrid density functional theory (DFT) and wave-function-in-DFT type for reaction energies and barriers. We show how the embedded calculations are accelerated in comparison to the corresponding supersystem calculations for realistic example reactions, using a new implementation of domain-based local pair natural orbital coupled cluster with single, double, and perturbative triple excitations [DLPNO-CCSD(T
0 )]. The embedded calculations yield results within an error margin below 4 kJ mol-1 for the reaction barrier and energy when compared to the supersystem calculation. The calculations can be executed in a user-friendly, black-box-like fashion with minimal manual input.- Published
- 2020
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21. No evidence for DNA N 6 -methyladenine in mammals.
- Author
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Douvlataniotis K, Bensberg M, Lentini A, Gylemo B, and Nestor CE
- Subjects
- Animals, Bacteria genetics, Chromatin Immunoprecipitation Sequencing, Mass Spectrometry, Single Molecule Imaging, Species Specificity, Adenosine analogs & derivatives, DNA Methylation, Mammals genetics
- Abstract
N
6 -methyladenine (6mdA) is a widespread DNA modification in bacteria. More recently, 6mdA has also been characterized in mammalian DNA. However, measurements of 6mdA abundance and profiles are often very dissimilar between studies, even when performed on DNA from identical mammalian cell types. Using comprehensive bioinformatics analyses of published data and novel experimental approaches, we reveal that efforts to assay 6mdA in mammals have been severely compromised by bacterial contamination, RNA contamination, technological limitations, and antibody nonspecificity. These complications render 6mdA an exceptionally problematic DNA modification to study and have resulted in erroneous detection of 6mdA in several mammalian systems. Together, our results strongly imply that the evidence published to date is not sufficient to support the presence of 6mdA in mammals., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)- Published
- 2020
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22. Erratum: "Automatic basis-set adaptation in projection-based embedding" [J. Chem. Phys. 150, 184104 (2019)].
- Author
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Bensberg M and Neugebauer J
- Published
- 2019
- Full Text
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23. Direct orbital selection for projection-based embedding.
- Author
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Bensberg M and Neugebauer J
- Abstract
Projection-based embedding (PbE) has become increasingly popular in recent years due to its simplicity and robustness. It is a very promising method for highly accurate calculations of reaction barriers and reaction energies via embedding of a correlated wavefunction or sophisticated density functional theory (DFT) method for the reaction center into a more cost effective DFT description of the environment. PbE enables an arbitrary partitioning of the supersystem orbitals into subsystems. In most applications so far, the selection of orbitals for the active system was directly linked to the selection of "active atoms." We propose an inexpensive approach that automatically selects orbitals as active that change during the reaction and that assigns all remaining orbitals to the environment. This approach is directly coupled to the reaction under investigation and does not rely on any specification of active atoms. We compare different variants of this approach for the selection of orbitals along the reaction path for embedding of Adamo and Barone's hybrid functional (known as PBE0) into Perdew, Burke, and Ernzerhof's exchange-correlation functional (PBE), a method dubbed as PBE0-in-PBE embedding, based on orbitalwise partial charges and the kinetic energy. The most successful comparison scheme is based on shellwise intrinsic atomic orbital charges. We show for a set of six reactions of different types that the corresponding errors in reaction energies and barriers converge quickly to zero with the extension of the active-orbital space.
- Published
- 2019
- Full Text
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24. Automatic basis-set adaptation in projection-based embedding.
- Author
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Bensberg M and Neugebauer J
- Abstract
Projection-based embedding (PbE) is an exact embedding method within density-functional theory (DFT) that has received increasing attention in recent years. Several different variants have been described in the literature, but no systematic comparison has been presented so far. The truncation of the basis is critical for the efficiency of this class of approaches. Here, we employ a basis-set truncation scheme previously used for level-shift embedding in a top-down fashion, and we present an own basis-set extension scheme for bottom-up type PbE. We compare its accuracy for the level-shift technique [Manby et al., J. Chem. Theory Comput. 8, 2564-2568 (2012)] and an empirically corrected variant, the external-orthogonality approach by Khait and Hoffmann [Annu. Rep. Comput. Chem. 8, 53-70 (2012)] and the approach based on the Huzinaga equation transferred to the DFT context [Hégely et al., J. Chem. Phys. 145, 064107 (2016)]. Concerning the reproduction in total energies, we show that the Huzinaga method yields the most stable results concerning a basis-set truncation in top-down embedding. For the practically more relevant calculation of energy differences, the efficient level-shift technique yields very promising results due to error cancellation. In bottom-up embedding, we observe convergence issues in cases where constraints in the Lagrange formalism cannot be fulfilled due to basis-set incompleteness.
- Published
- 2019
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25. A multi-stage process including transient polyploidization and EMT precedes the emergence of chemoresistent ovarian carcinoma cells with a dedifferentiated and pro-inflammatory secretory phenotype.
- Author
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Rohnalter V, Roth K, Finkernagel F, Adhikary T, Obert J, Dorzweiler K, Bensberg M, Müller-Brüsselbach S, and Müller R
- Subjects
- Antineoplastic Agents pharmacology, Cell Cycle Checkpoints drug effects, Cell Cycle Checkpoints genetics, Cell Dedifferentiation genetics, Cell Division drug effects, Cell Division genetics, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Cellular Senescence drug effects, Cellular Senescence genetics, Drug Resistance, Neoplasm genetics, Epithelial-Mesenchymal Transition genetics, Female, Flow Cytometry, Humans, Microscopy, Fluorescence, Nuclear Proteins genetics, Nuclear Proteins metabolism, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Time Factors, Time-Lapse Imaging, Carboplatin pharmacology, Cell Dedifferentiation drug effects, Drug Resistance, Neoplasm drug effects, Epithelial-Mesenchymal Transition drug effects, Inflammation Mediators metabolism, Polyploidy
- Abstract
DNA-damaging drugs induce a plethora of molecular and cellular alterations in tumor cells, but their interrelationship is largely obscure. Here, we show that carboplatin treatment of human ovarian carcinoma SKOV3 cells triggers an ordered sequence of events, which precedes the emergence of mitotic chemoresistant cells. The initial phase of cell death after initiation of carboplatin treatment is followed around day 14 by the emergence of a mixed cell population consisting of cycling, cell cycle-arrested and senescent cells. At this stage, giant cells make up >80% of the cell population, p21 (CDKN1A) in strongly induced, and cell numbers remain nearly static. Subsequently, cell death decreases, p21 expression drops to a low level and cell divisions increase, including regular mitoses of giant cells and depolyploidization by multi-daughter divisions. These events are accompanied by the upregulation of stemness markers and a pro-inflammatory secretory phenotype, peaking after approximately 14 days of treatment. At the same time the cells initiate epithelial to mesenchymal transition, which over the subsequent weeks continuously increases, concomitantly with the emergence of highly proliferative, migratory, dedifferentiated, pro-inflammatory and chemoresistant cells (SKOV3-R). These cells are anchorage-independent and grow in a 3D collagen matrix, while cells on day 14 do not survive under these conditions, indicating that SKOV3-R cells were generated thereafter by the multi-stage process described above. This process was essentially recapitulated with the ovarian carcinoma cell line IGROV-1. Our observations suggest that transitory cells characterized by polyploidy, features of stemness and a pro-inflammatory secretory phenotype contribute to the acquisition of chemoresistance.
- Published
- 2015
- Full Text
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26. How healthy are our emergency departments?
- Author
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Joe K, Kennedy M, and Bensberg M
- Subjects
- Data Collection, Female, Humans, Male, Morale, Reward, Safety Management, Suburban Population, Victoria, Workforce, Workplace psychology, Workplace standards, Attitude of Health Personnel, Emergency Service, Hospital standards, Job Satisfaction, Occupational Health, Personnel, Hospital psychology
- Abstract
Objective: To demonstrate a comprehensive workplace health survey is able to identify indicators that contribute to staff workplace welfare., Methods: Analysis of a VicHealth workplace health survey distributed to seven suburban emergency departments. Respondents rated multiple workplace health indicators in terms of perceived importance and perceived performance. A satisfaction rating and performance gap for each indicator was calculated., Results: There was a 64% response rate to 500 surveys. Staff rated a safe environment, professional standards, and staff morale the most important factors for workplace health. They were most satisfied with the flexibility of work arrangements (85.6%) and leadership (79.9%), and were least satisfied with the performance management of staff (68.5%) and job satisfaction and morale (67.2%). The largest gaps between perceived importance and performance were in the provision of safe well-lit parking, staff morale, and the use of reward and recognition systems., Conclusion: The VicHealth survey was an effective tool in identifying indicators that contribute to staff workplace health. Quantifiable findings allowed interdepartmental comparison and may be useful in focusing on improvements in organizational structure.
- Published
- 2002
- Full Text
- View/download PDF
27. Health promotion-who, us? Developing health promoting emergency departments.
- Author
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Bensberg M and Kennedy M
- Subjects
- Focus Groups, Humans, Organizational Innovation, Program Development, Victoria, Emergency Service, Hospital organization & administration, Health Promotion organization & administration
- Abstract
This paper describes the initiation of Victoria's Health Promoting Emergency Departments (HPEDs) Program, involving seven of Melbourne's Emergency Departments (EDs). The Program aims to integrate health promotion into the function of EDs, to complement the clinical and curative emergency care that they already provide. A development phase identified the means of achieving this and involved establishing a multi-disciplinary Steering Committee and engaging health promotion specialists to record the opportunities for health promotion within the ED context. A literature review, and consultations with ED staff (focus groups and surveys) and other stakeholders were conducted. A concept paper was published and the development phase findings were documented, including recommendations on the future of the Program.
- Published
- 2001
- Full Text
- View/download PDF
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