Search

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.

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.

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.)

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.

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.

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).)

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.