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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.

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/).)

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.

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.

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.

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.)

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(T 0 ) 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(T 0 ) 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(T 0 ) 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(T 0 ) 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.

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.

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.

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.

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.

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.

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.

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).)

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.

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.

Nanoscopic systems exhibit diverse molecular substructures by which they facilitate specific functions. Theoretical models of them, which aim at describing, understanding, and predicting these capabilities, are difficult to build. Viable quantum-classical hybrid models come with specific challenges regarding atomistic structure construction and quantum region selection. Moreover, if their dynamics are mapped onto a state-to-state mechanism such as a chemical reaction network, its exhaustive exploration will be impossible due to the combinatorial explosion of the reaction space. Here, we introduce a "quantum magnifying glass" that allows one to interactively manipulate nanoscale structures at the quantum level. The quantum magnifying glass seamlessly combines autonomous model parametrization, ultra-fast quantum mechanical calculations, and automated reaction exploration. It represents an approach to investigate complex reaction sequences in a physically consistent manner with unprecedented effortlessness in real time. We demonstrate these features for reactions in bio-macromolecules and metal-organic frameworks, diverse systems that highlight general applicability., (© 2024. The Author(s).)

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.

Genetic variations and DNA modification are two common dominant factors ubiquitous across the entire human genome and induce human disease, especially through static genetic variations in DNA or RNA that cause human genetic diseases. DNA N6-methyladenosine (6mA) methylation, as a new epigenetic modification mark, has been widely studied for regulatory biological processes in humans. However, the effect of DNA modification on dynamic transcriptional genetic variations from DNA to RNA has rarely been reported. Here, we identified DNA, RNA and transcriptional genetic variations from Illumina short-read sequencing data in East Asian samples (HX1 and AK1) and detected global DNA 6mA modification using single-molecule, real-time sequencing (SMRT) data. We decoded the effects of DNA 6mA modification on transcriptional genetic variations in East Asian samples and the results were extensively verified in the HeLa cell line. DNA 6mA modification had a stabilized distribution in the East Asian samples and the methylated genes were less likely to mutate than the non-methylated genes. For methylated genes, the 6mA density was positively correlated with the number of variations. DNA 6mA modification had a selective effect on transcriptional genetic variations from DNA to RNA, in which the dynamic transcriptional variations of heterozygous (0/1 to 0/1) and homozygous (1/1 to 1/1) were significantly affected by 6mA modification. The effect of DNA methylation on transcriptional genetic variations provides new insights into the influencing factors of DNA to RNA transcriptional regulation in the central doctrine of molecular biology. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations on atomistic systems have evolved into a standard approach to studying molecular matter. These calculations often involve a significant amount of manual input and expertise, although most of this effort could be automated, which would alleviate the need for expertise in software and hardware accessibility. Here, we present the AutoRXN workflow, an automated workflow for exploratory high-throughput electronic structure calculations of molecular systems, in which (i) density functional theory methods are exploited to deliver minimum and transition-state structures and corresponding energies and properties, (ii) coupled cluster calculations are then launched for optimized structures to provide more accurate energy and property estimates, and (iii) multi-reference diagnostics are evaluated to back check the coupled cluster results and subject them to automated multi-configurational calculations for potential multi-configurational cases. All calculations are carried out in a cloud environment and support massive computational campaigns. Key features of all components of the AutoRXN workflow are autonomy, stability, and minimum operator interference. We highlight the AutoRXN workflow with the example of an autonomous reaction mechanism exploration of the mode of action of a homogeneous catalyst for the asymmetric reduction of ketones. [ABSTRACT FROM AUTHOR]

Background: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. Methods: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. Results: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. Conclusions: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers. [ABSTRACT FROM AUTHOR]

Autonomous reaction network exploration algorithms offer a systematic approach to explore mechanisms of complex chemical processes. However, the resulting reaction networks are so vast that an exploration of all potentially accessible intermediates is computationally too demanding. This renders brute-force explorations unfeasible, while explorations with completely pre-defined intermediates or hard-wired chemical constraints, such as element-specific coordination numbers, are not flexible enough for complex chemical systems. Here, we introduce a STEERING WHEEL to guide an otherwise unbiased automated exploration. The STEERING WHEEL algorithm is intuitive, generally applicable, and enables one to focus on specific regions of an emerging network. It also allows for guiding automated data generation in the context of mechanism exploration, catalyst design, and other chemical optimization challenges. The algorithm is demonstrated for reaction mechanism elucidation of transition metal catalysts. We highlight how to explore catalytic cycles in a systematic and reproducible way. The exploration objectives are fully adjustable, allowing one to harness the STEERING WHEEL for both structure-specific (accurate) calculations as well as for broad high-throughput screening of possible reaction intermediates. Automated reaction exploration is the key to systematic elucidation of chemical mechanisms. Here, the authors introduce a generally applicable algorithm to steer an automated exploration towards region of interest in chemical reaction space. [ABSTRACT FROM AUTHOR]

Study Objective: To describe the opportunities for health promotion in emergency departments (EDs)., Methods: A comprehensive literature review and consultation with ED staff (seven focus groups) and other health professionals (workshop)., Results: Opportunities for patient health information and education within EDs are described in the literature. In contrast, the health promoting hospitals literature showcases integrated approaches for health promotion, emphasizing organisational structures, and culture changes to support effective health promotion. This type of integration has not developed in EDs, where individual issues based health promotion projects have emerged. ED staff readily described the:existing health promotion interventions and possible improvements and opportunities for potential health promotion interventions related to the needs of their patients, the community or their organisation. Other health professionals supported EDs taking a greater role in health promotion and suggested organisational partnerships that would assist in developing this., Conclusion: There are numerous opportunities to enhance health promotion in EDs. With support, EDs could deliver comprehensive health promotion programs for patients, staff, and communities.

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.

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.

Subsystem density-functional theory compiles a set of features that allow for efficiently calculating properties of very large open-shell radical systems such as organic radical crystals, proteins, or deoxyribonucleic acid stacks. It is computationally less costly than correlated ab initio wave function approaches and can pragmatically avoid the overdelocalization problem of Kohn–Sham density-functional theory without employing hard constraints on the electron-density. Additionally, subsystem density-functional theory calculations commonly start from isolated fragment electron densities, pragmatically preserving a priori specified subsystem spin-patterns throughout the calculation. Methods based on subsystem density-functional theory have seen a rapid development over the past years and have become important tools for describing open-shell properties. In this Perspective, we address open questions and possible developments toward challenging future applications in connection with subsystem density-functional theory for spin-dependent properties. [ABSTRACT FROM AUTHOR]

The universality of DNA methylation as an epigenetic regulatory mechanism belongs to all biological kingdoms. However, while eukaryotic systems have been the primary focus of DNA methylation studies, the molecular mechanisms in prokaryotes are less known. Nevertheless, DNA methylation in prokaryotes plays a pivotal role in many cellular processes such as defense systems against exogenous DNA, cell cycle dynamics, and gene expression, including virulence. Thanks to single-molecule DNA sequencing technologies, genome-wide identification of methylated DNA is becoming feasible on a large scale, providing the possibility to investigate more deeply the presence, variability, and roles of DNA methylation. Here, we present an overview of the multifaceted roles of DNA methylation in prokaryotes and suggest research directions and tools which can enable us to better understand the contribution of DNA methylation to prokaryotic genome evolution and adaptation. In particular, we emphasize the need to understand the presence and role of transgenerational inheritance, as well as the impact of epigenomic signatures on adaptation and genome evolution. Research directions and the importance of novel computational tools are underlined. [ABSTRACT FROM AUTHOR]

Under national or state-based legislation, local governments are commonly required to prepare municipal health and wellbeing plans. Yet, the issues these plans aim to address are often complex, and programmatic planning approaches traditionally used by practitioners struggle to engage with such complexity as they assume these issues can be 'solved' in isolation. Systems thinking is increasingly being used as an approach to deal with those struggles more effectively, yet little is known about whether local governments and other stakeholders think systems approaches are feasible and acceptable in practice. This study tested a systems thinking approach to gauge if it could better address complex place-based health and wellbeing issues, such as to reduce noncommunicable diseases. Guided by a systems change framework, the approach comprised a facilitated systemic inquiry and rich picture process involving diverse stakeholders in a remote municipality in the Australian state of Tasmania. Among the participants there was broad support for the systems approach tested and they thought it was effective for increasing systems thinking capacity, collaboratively revealing systemic issues, and identifying opportunities to address those issues. They valued the rich picture because it created shared understandings of local issues. The findings suggest more is needed from macro-level policy to support place-based stakeholders to undertake systems approaches in practice, which could result in more sustainable and effective systems change required to improve health and wellbeing outcomes. The findings have implications for theory, research, and practice across interdisciplinary fields concerned with placed-based systems change, especially in rural and remote municipalities. [ABSTRACT FROM AUTHOR]

Purpose: Investing in prevention could be of great benefit to public health. Especially for people with health risks, such as overweight, depressive symptoms, low social-economic status or people who experience loneliness or a sedentary lifestyle. In the Netherlands, different parties are responsible for financing and organising selective and indicated preventive interventions: the government, municipalities and health insurance companies. The aim of this study was two-fold: First, to describe the transition towards a sustainable prevention infrastructure. And second, to gain insight into barriers and facilitators associated with intersectoral collaboration regarding organising prevention for high-risk groups. Design/methodology/approach: A longitudinal qualitative study was conducted among collaborative networks working together to build a prevention infrastructure. During a five-year study period, 86 semi-structured interviews were held. The COM-B model was used for data analysis. Findings: Barriers to intersectoral collaboration are: unknown (cost-)effectiveness, limited incentives to invest in collaboration, lack of clarity about responsibilities, differences in priorities and organisational culture between municipalities and health insurers. Facilitators are commitment, trust, sharing knowledge between parties, meeting regularly within the network and acknowledgement of mutual responsibilities. Also, national policy interventions targeted at the development of regional prevention infrastructures facilitated collaboration. Originality/value: This study shows that collaboration regarding prevention is becoming increasingly common. It can be concluded that the transition towards a sustainable prevention infrastructure has started. The relationship between key stakeholders, like municipalities and health insurers, is generally stronger than it was five years ago. They have a better understanding of each other's interests and expectations. [ABSTRACT FROM AUTHOR]

It is now widely accepted that many of the problems we face in public health are complex, from chronic disease to COVID-19. To grapple with such complexity, researchers have turned to both complexity science and systems thinking to better understand the problems and their context. Less work, however, has focused on the nature of complex solutions, or intervention design, when tackling complex problems. This paper explores the nature of system intervention design through case illustrations of system action learning from a large systems level chronic disease prevention study in Australia. The research team worked with community partners in the design and implementation of a process of system action learning designed to reflect on existing initiatives and to reorient practice towards responses informed by system level insights and action. We were able to observe and document changes in the mental models and actions of practitioners and in doing so shine a light on what may be possible once we turn our attention to the nature and practice of system interventions. [ABSTRACT FROM AUTHOR]

We present a method for obtaining origin-independent electronic circular dichroism (ECD) in the length-gauge representation LG(OI) without the usage of London atomic orbitals. This approach builds upon the work by Caricato [J. Chem. Phys. 153, 151101 (2020)] and is applied to rotatory strengths and ECD spectra from damped response theory. Numerical results are presented for time-dependent Hartree–Fock and density-functional theory, the second-order algebraic diagrammatic construction method, and linear-response coupled-cluster theory with singles and approximate doubles. We can support the finding that the common choice of placing the gauge origin in the center of mass of a molecule in conventional length-gauge calculations involving chiroptical properties might not be optimal and show that LG(OI) is a valuable alternative for the origin-independent calculation of ECD spectra. We show that, for a limited test set, the convergence of the rotatory strengths calculated with the LG(OI) approach toward the basis-set limit tends to be faster than for the established velocity gauge representation. Relationships between the sum-over-states expression of the optical rotation in the LG(OI) framework and its representation in terms of response functions are analyzed. [ABSTRACT FROM AUTHOR]

N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex structures of 6mA demethylase C. elegans NMAD-1A, a canonical isoform of NMAD-1 (F09F7.7). Biochemical results revealed that NMAD-1A prefers 6mA Bubble or Bulge DNAs. Structural studies of NMAD-1A revealed an unexpected "stretch-out" conformation of its Flip2 region, a conserved element that is usually bent over the catalytic center to facilitate substrate base flipping in other DNA demethylases. Moreover, the wide channel between the Flip1 and Flip2 of the NMAD-1A explained the observed preference of NMAD-1A for unpairing substrates, of which the flipped 6mA was primed for catalysis. Structural analysis and mutagenesis studies confirmed that key elements such as carboxy-terminal domain (CTD) and hypothetical zinc finger domain (ZFD) critically contributed to structural integrity, catalytic activity, and nucleosome binding. Collectively, our biochemical and structural studies suggest that NMAD-1A prefers to regulate 6mA in the unpairing regions and is thus possibly associated with dynamic chromosome regulation and meiosis regulation. [ABSTRACT FROM AUTHOR]

Background: Engineers, educators, and policymakers throughout the United States have been trying to diversify engineering for decades. In response to this shared aspiration, professionals and educators from engineering and other STEM disciplines have constructed Broadening Participation as a phenomenon involving individual and collective efforts in the form of both research and practice. Purpose: The purpose of this paper is to advance the science of Broadening Participation by explaining the relationship between research and practice in this context. Scope: As part of a larger project funded by the National Science Foundation focused on Broadening Participation-efforts aimed at Black Americans, we used Ecological Systems Theory to organize insights from literature, interviews with subject matter experts, and the collective sensemaking of our author team. Discussion/Conclusions: Our insights highlight how Broadening Participation is a sociopolitical phenomenon resulting from social, political, and historical influences related to diversifying engineering. We share these insights in language familiar to engineers (i.e., systems thinking) in hopes to advance stakeholders' understanding of Broadening Participation. In doing so, our aim is to give the field of engineering an alternative heuristic for conceptualizing, discussing, and approaching Broadening Participation. Though this paper is primarily written from the perspective of Black Americans, it is intended to be useful to the field broadly. [ABSTRACT FROM AUTHOR]

Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To recognise that emergency nurses have an opportunity to integrate health promotion in the care they provide • To understand the barriers to health promotion in emergency care settings • To consider how you could provide further health promotion to patients in your practice setting Background: Emergency departments (EDs) afford 'teachable moments' for health behaviour change, but staff may not see themselves as public health practitioners and it can be challenging to undertake health promotion activities in emergency care settings. Furthermore, the evidence on health promotion in these settings is limited. Aim: To investigate the views and experiences of emergency nurses and ambulance service paramedics regarding health promotion in emergency care settings. Method: A convenience sample of emergency nurses (n=3) and ambulance service paramedics (n=3) was recruited. An inductive and descriptive qualitative study design using semi-structured interviews and thematic analysis was employed. Findings: The participants understood health promotion and were willing to have conversations about it with patients. However, they cited several barriers to health promotion, including understaffing, a lack of understanding of the relevance of health promotion among staff, a lack of training and information, and the sensitivity of topics such as body weight and sexual health. Lack of time was not cited as a barrier. Conclusion: There are opportunities for developing the health promotion aspect of practice in emergency care settings, where staff and patients would benefit from a more structured, system-wide approach to health promotion. [ABSTRACT FROM AUTHOR]

N6-methyladenine (6mA) in the DNA is a conserved epigenetic mark with various cellular, physiological and developmental functions. Although the presence of 6mA was discovered a few years ago in the nuclear genome of distantly related animal taxa and just recently in mammalian mitochondrial DNA (mtDNA), accumulating evidence at present seriously questions the presence of N6-adenine methylation in these genetic systems, attributing it to methodological errors. In this paper, we present a reliable, PCR-based method to determine accurately the relative 6mA levels in the mtDNA of Caenorhabditis elegans, Drosophila melanogaster and dogs, and show that these levels gradually increase with age. Furthermore, daf-2(−)-mutant worms, which are defective for insulin/IGF-1 (insulin-like growth factor) signaling and live twice as long as the wild type, display a half rate at which 6mA progressively accumulates in the mtDNA as compared to normal values. Together, these results suggest a fundamental role for mtDNA N6-adenine methylation in aging and reveal an efficient diagnostic technique to determine age using DNA. [ABSTRACT FROM AUTHOR]