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Interacting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here, I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors, and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematode Caenorhabditis elegans. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.

Background: Accurate diagnosis of latent tuberculosis infected (LTBI) individuals is important in identifying individuals at risk of developing active tuberculosis. Current diagnosis of LTBI routinely relies on the detection and measurement of immune responses using the Tuberculin Skin Test (TST) and interferon gamma release assays (IGRAs). However, IGRA, which detects Mycobacterium tuberculosis specific IFN-γ, is associated with frequent indeterminate results, particularly in immunosuppressed patients. There is a need to identify more sensitive LTBI point of care diagnostic biomarkers. The aim of this study was to assess the validity of early secreted antigen target 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) stimulated plasma to identify additional cytokines and chemokines as potential biomarkers of LTBI.Method: The levels of 27 cytokines and chemokines were measured by Bio-Plex Pro cytokine, chemokine and growth factor assay in ESAT-6 and CFP-10 co-stimulated plasma from 20 LTBI participants with positive IGRA (Quantiferon TB Gold plus) and 20 healthy controls with negative IGRA. Traditional ELISA was used to validate the abundance of the best performing markers in 70 LTBI and 72 healthy participants. All participants were HIV negative.Results: We found that Interleukin 1 receptor antagonist (IL1ra) (p = 0.0056), Interleukin 2 (IL-2) (p < 0.0001), Interleukin 13 (IL-13) (p < 0.0001), Interferon gamma-induced protein 10 (IP-10) (p < 0.0001), and Macrophage inflammatory protein-1 beta (MIP1b) (p = 0.0010) were significantly higher in stimulated plasma of LTBI compared to healthy individuals. Stimulated plasma IL-2 (cutoff 100 pg/mL), IP-10 (cutoff 300 pg/mL) and IL-13 (5 pg/mL) showed potential in diagnosing LTBI with PPV = 100%, 0.89.4%, and 80.9% and NPV = 86.9%, 0.85.7%, and 84.2%, respectively.Conclusion: Our data shows that co-stimulating whole blood with ESAT-6 and CFP-10 may help distinguish LTBI from healthy individuals. We also identified IL-2 and IP-10 as potential biomarkers that could be added to the currently used IFN-γ release assays in detection of LTBI.

Digital twins are made of a real-world component where data is measured and a virtual component where those measurements are used to parameterize computational models. There is growing interest in applying digital twins-based approaches to optimize personalized treatment plans and improve health outcomes. The integration of artificial intelligence is critical in this process, as it enables the development of sophisticated disease models that can accurately predict patient response to therapeutic interventions. There is a unique and equally important application of AI to the real-world component of a digital twin when it is applied to medical interventions. The patient can only be treated once, and therefore, we must turn to the experience and outcomes of previously treated patients for validation and optimization of the computational predictions. The physical component of a digital twins instead must utilize a compilation of available data from previously treated cancer patients whose characteristics (genetics, tumor type, lifestyle, etc.) closely parallel those of a newly diagnosed cancer patient for the purpose of predicting outcomes, stratifying treatment options, predicting responses to treatment and/or adverse events. These tasks include the development of robust data collection methods, ensuring data availability, creating precise and dependable models, and establishing ethical guidelines for the use and sharing of data. To successfully implement digital twin technology in clinical care, it is crucial to gather data that accurately reflects the variety of diseases and the diversity of the population.

Objective In sub-Saharan Africa (SSA), multiple factors contribute to the considerable burden of mental health disorders among adolescents, highlighting the need for interventions that address underlying risks at multiple levels. We reviewed evidence of the effectiveness of community or family-level interventions, with and without individual level interventions, on mental health disorders among adolescents in SSA.Design Systematic review using the Grades of Recommendation, Assessment, Development and Evaluation approach.Data sources A systematic search was conducted on Cochrane Library, MEDLINE, EMBASE, PSYCINFO and Web of Science up to 31 March 2021.Eligibility criteria Studies were eligible for inclusion in the review if they were randomised controlled trials (RCTs) or controlled quasi-experimental studies conducted in sub-Saharan African countries and measured the effect of an intervention on common mental disorders in adolescents aged 10–24 years.Data extraction and synthesis We included studies that assessed the effect of interventions on depression, anxiety, post-traumatic stress disorder and substance abuse. Substance abuse was only considered if it was measured alongside mental health disorders. The findings were summarised using synthesis without meta-analysis, where studies were grouped according to the type of intervention (multi-level, community-level) and participants.Results Of 1197 studies that were identified, 30 studies (17 RCTs and 3 quasi-experimental studies) were included in the review of which 10 delivered multi-level interventions and 20 delivered community-level interventions. Synthesised findings suggest that multi-level interventions comprise economic empowerment, peer-support, cognitive behavioural therapy were effective in improving mental health among vulnerable adolescents. Majority of studies that delivered interventions to community groups reported significant positive changes in mental health outcomes.Conclusions The evidence from this review suggests that multi-level interventions can reduce mental health disorders in adolescents. Further research is needed to understand the reliability and sustainability of these promising interventions in different African contexts.PROSPERO registration number CRD42021258826.

For the present lab demonstration, we have developed fluorescent indicators to detect the end point in microscale redox titration of ferrous ions in permanganometry, cerimetry, and dichrometry. Microscale redox titrations were carried out effectively in micromolar(µM) concentrations and semi-microvolumes of the analytes. At the end point, fluorescent indicating action was confirmed successfully by the quenching of bluish-white fluorescence of poly-N-phenyl anthranilic acid (PNPA-H) and N-phenyl anthranilic acid (NPA-H). The fluorescence turn-off mechanism was due to the oxidation of protonated diphenyl benzidine dicarboxylic acid units (fluorescent) to diphenyl diquinoid dicarboxylicacid units (nonfluorescent) of PNPA-H and NPA-H. Standard distribution curves and statistical methods have revealed that fluorescent indicators have good precision and accuracy for the estimated masses. Students' responses to micromolar titration and semi-microvolume titrations using fluorescent indicators were also analyzed. Fluorescent indicators like PNPA-H and NPA-H provide an excellent opportunity for microscale volumetric estimation of ferrous ions, which is otherwise difficult using conventional indicators. The indicating action of fluorescent indicators for microscale redox titrations was beneficial in reducing the time of experiment and chemicals used. Estimating microscale quantities of mass in the lab via a simple microscale redox titration would encourage students to practice green chemistry.

Dylan M Buller,1,&ast; Maria Antony,2,&ast; Benjamin T Ristau1 1Division of Urology, UConn Health, Farmington, CT, USA; 2University of Connecticut School of Medicine, Farmington, CT, USA&ast;These authors contributed equally to this workCorrespondence: Benjamin T Ristau, Division of Urology, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030, Tel +1 860 679 3438, Fax +1 860 679 6109, Email benristaumd@gmail.comAbstract: Locally and regionally advanced renal cell carcinoma (RCC) can recur at high rates even after visually complete resection of primary disease. Both targeted therapies and immunotherapies represent potential agents that might help reduce recurrence of RCC in these patients. This paper reviews the current body of evidence defining their potential impact and examines the large Phase III randomized clinical trials that have been performed to assess the safety and efficacy of these systemic therapies in the adjuvant setting. Given that the findings from these trials have been predominantly negative, this paper also explores the role of other potential adjuvant agents, including single and combination agent targeted therapies and immunotherapies, whose use is currently limited to metastatic RCC. Finally, the use of radiation therapy and the use of advanced imaging modalities in RCC are also considered.Keywords: renal cell carcinoma, adjuvant therapy, targeted therapy, immunotherapy, radiation

Arrested replication forks, when restarted by homologous recombination, result in error-prone DNA syntheses and non-allelic homologous recombination. Fission yeast RTS1 is a model fork barrier used to probe mechanisms of recombination-dependent restart. RTS1 barrier activity is entirely dependent on the DNA binding protein Rtf1 and partially dependent on a second protein, Rtf2. Human RTF2 was recently implicated in fork restart, leading us to examine fission yeast Rtf2’s role in more detail. In agreement with previous studies, we observe reduced barrier activity upon rtf2 deletion. However, we identified Rtf2 to be physically associated with mRNA processing and splicing factors and rtf2 deletion to cause increased intron retention. One of the most affected introns resided in the rtf1 transcript. Using an intronless rtf1, we observed no reduction in RFB activity in the absence of Rtf2. Thus, Rtf2 is essential for correct rtf1 splicing to allow optimal RTS1 barrier activity.

The aim of this study is to show that the geometry of titanium dioxide (TiO2) nanotubes has an inevitable role in photocatalytic activity. The TiO2 nanotubes were synthesized by anodization technique. Au nanoparticles (AuNPs) were spin-coated onto the surface of these nanotubes. The photocatalytic activity study was conducted using methylene blue dye under UV light and sunlight. In contrast to the obtained results under UV light irradiation, the photocatalytic activity under sunlight irradiation of AuNPs-coated TiO2 nanotubes was much higher. The nanotubes showcased improved visible light absorption and photocatalysis under sunlight condition due to the SPR effect of AuNPs. Compared to other samples, the nanotubes prepared at 600 s (second) duration had an intrinsic geometry which exhibited high photocatalytic activity under sunlight irradiation. These results indicate that the maximum photocatalytic efficiency of TiO2 nanotubes can be achieved by carefully designing the nanotube geometry.

Profiling of human DNA polymerase Polε and Polα demonstrates their roles in leading and lagging strand DNA synthesis, and their independent measures allowed accurate predictions of replication dynamics and effects of transcription.

Abstract Background Many marine man-made structures (MMS), such as oil and gas platforms or offshore wind turbines, are nearing their ‘end-of-life’ and require decommissioning. Limited understanding of MMS decommissioning effects currently restricts the consideration of alternative management possibilities, often leaving complete removal as the only option in certain parts of the world. This evidence-base describes the ecosystem effects of marine MMS whilst in place and following cessation of operations, with a view to informing decision-making related to their potential decommissioning. Method The protocol used to create this map was published a priori. Systematic searches of published, literature in English were conducted using three bibliographic databases, ten specialist organisational websites or repositories, and one search engine, up to early 2021. A total of 15,697 unique articles were identified as potentially relevant to our research questions, of which 2,230 were screened at the full-text level. Of that subset, 860 articles met all pre-defined eligibility criteria. A further 119 articles were identified through “snowballing” of references from literature reviews. The final database consists of 979 articles. For each article included, metadata were extracted for key variables of interest and coded into a database. Review findings The vast majority of eligible articles related to the presence of MMS (96.2%), while just 5.8% considered decommissioning. Overall, articles mainly considered artificial reefs (51.5% of all articles) but increasingly oil and gas (22%), shipwrecks (15.1%) and offshore wind (13.1%). Studies were distributed globally, but the majority focused on the United States, single countries within Europe, Australia, Brazil, China, and Israel; 25 studies spanned multiple countries. Consequently, the bulk of the studies focused on the North Atlantic (incl. Gulf of Mexico, North Sea, and Mediterranean Sea) and North Pacific Oceans. A further 12 studies had a global scope. Studies in majority reported on fish (53%) and invertebrates (41%), and were disproportionately focused on biological (81%) and ecological (48%) impacts. Physico-chemical (13%), habitat (7%), socio-cultural (7%), economic (4%) and functional (8%) outcomes have received less attention. The number of decommissioning studies has been increasing since ca. 2012 but remains noticeably low. Studies mostly focus on oil and gas infrastructures in the USA (Gulf of Mexico) and Northern Europe (North Sea), covering 9 different decommissioning options. Conclusions This systematic map, the first of its kind, reveals a substantial body of peer-reviewed evidence relating to the presence of MMS in the sea and their impacts, but with considerable bias toward biological and ecological outcomes over abiotic and socio-economic outcomes. The map reveals extremely limited direct evidence of decommissioning effects, likely driven at least in part by international policy preventing consideration of a range of decommissioning options beyond complete removal. Despite evidence of MMS impacts continuing to grow exponentially since the early 1970s, this map reveals key gaps in evidence to support best practice in developing decommissioning options that consider environmental, social and economic effects. Relevant evidence is required to generate greater understanding in those areas and ensure decommissioning options deliver optimal ecosystem outcomes.

The link between neural development and tumourigenesis in adult glioma remains unclear. Here, the authors monitor the developmental stages of Sox2 + /− stem cells from a mouse model using single-cell RNA sequencing and suggest the acquisition of embryonic-like states in the adult glioma development.

Summary: Efficient replication of terminal DNA is crucial to maintain telomere stability. In fission yeast, Taz1 and the Stn1-Ten1 (ST) complex play prominent roles in DNA-ends replication. However, their function remains elusive. Here, we have analyzed genome-wide replication and show that ST does not affect genome-wide replication but is crucial for the efficient replication of a subtelomeric region called STE3-2. We further show that, when ST function is compromised, a homologous recombination (HR)-based fork restart mechanism becomes necessary for STE3-2 stability. While both Taz1 and Stn1 bind to STE3-2, we find that the STE3-2 replication function of ST is independent of Taz1 but relies on its association with the shelterin proteins Pot1-Tpz1-Poz1. Finally, we demonstrate that the firing of an origin normally inhibited by Rif1 can circumvent the replication defect of subtelomeres when ST function is compromised. Our results help illuminate why fission yeast telomeres are terminal fragile sites.

The authors uncover synthetic lethality between TP53 and ENDOD1, which contains an atypical endonuclease domain. Co-depleted G1 cells accumulate single stranded DNA and die. Combined with xenograft data the work identifies ENDOD1 as a potential cancer-specific SL drug discovery target.

Growth in collaborative research raises difficulties for those tasked with research evaluation, particularly in situations where outcomes are slow to emerge. This article presents the 'Diversity Approach to Research Evaluation' (DARE) as a novel way to assess how researchers engaged in knowledge creation and application work together as teams. DARE provides two important insights: first, it reveals the differences in background and experience between individual team members that can make research collaboration both valuable and challenging; second, DARE provides early insights into how team members are working together. DARE achieves these insights by analysing team diversity and cohesiveness in five dimensions, building on Boschma's multi-dimensional concept of proximity. The method we propose combines narratives, maps, and indicators to facilitate the study of research collaboration. The article introduces the DARE method and pilots an initial operationalization through the study of two grant-funded biomedical research projects led by researchers in the UK. Suggestions for further development of the approach are discussed.

Stable epigenetic changes are relatively rare. Here the authors report that mating induces stable silencing of a single-copy transgene in C. elegans. Components of small RNA silencing are required for this stable silencing.

Single-molecule localisation microscopy (SMLM) uses software to extract super-resolved positions from microscope images of fluorescent molecules. These localisations can then be used to render super-resolution images or analysed to extract information about molecular behaviour. The GDSC SMLM software provides a set of tools for analysing SMLM data in a single cross-platform environment. The software identifies fluorescent molecules in raw microscope images and localises their positions using stages of spot detection, spot fitting and spot rejection. The resulting localisation data set can then be visualised, cropped and filtered. A suite of downstream analysis tools enable the user to perform single-particle tracking, cluster analysis and drift correction. In addition, GDSC SMLM also provides utility tools that enable modelling of EM-CCD and sCMOS cameras as well as point spread functions (PSFs) for data simulation. The software is written in Java and runs as a collection of plugins for the ImageJ software.

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free (GF) mice, and in GF mice reconstituted with normal gut microbiota (XGF). Liver mass restoration, hepatocyte proliferation, and immune response were assessed following 70% PHx. Hepatic matrisome and collagen gene expression were also analyzed. Reduced liver weight/body weight ratio, mitotic count, and hepatocyte proliferative index at 72 h post PHx in GF mice were preceded by reduced expression of cytokine receptor genes Tnfrsf1a and Il6ra, and Hgf gene at 3 h post PHx. In XGF mice, these indices were significantly higher than in GF mice, and similar to that of control mice, indicating normal liver regeneration. Differentially expressed genes (DEGs) of the matrisome were lower in GF compared to XGF mice at both 3 h and 72 h post PHx. GF mice also demonstrated lower collagen expression, with significantly lower expression of Col1a1, Col1a2, Col5a1, and Col6a2 compared to WT mice at 72 h post PHx. In conclusion, enhanced liver regeneration and matrisome expression in XGF mice suggests that interaction of the gut microbiota and matrisome may play a significant role in the regulation of hepatic remodeling during the regenerative process.

Telomeres suppress the DNA damage response at chromosome ends. Here the authors show that in budding yeast the activity of the MRX complex in DNA repair and DNA damage signaling is inhibited by telomeric protein Rif2 via a short motif at the N-terminus.

Eric Kees et al. explore whether ecological competition differs between surface-attached biofilms and planktonic culture using two differentially-reproducing strains of Shewanella oneidensis. They observed that, regardless of different growth rates, the first bacterial species to colonize a surface would persist and would not be excluded by a faster growing competitor.

Abstract Background Numerous man-made structures (MMS) have been installed in various parts of the ocean (e.g. oil and gas structures, offshore wind installations). Many are now at, or nearing, the end of their intended life. Currently, we only have a limited understanding of decommissioning effects. In many locations, such as the North Sea, regulations restrict decommissioning options to complete removal, with little consideration of alternative management options might offer. To generate a reliable evidence-base to inform the decision-making processes pertaining to marine MMS management, we propose a wide-encompassing systematic map of published research on the ecosystem effects (including ecosystem services) of marine MMS while in place and following cessation of operations (i.e. including effects of alternative decommissioning options). This map is undertaken as part of the UKRI DREAMS project which aims to develop a system to show the relative effects of implementing different decommissioning strategies in the North Sea. Method For the purpose of this map, we will keep our focus global, in order to subsequently draw comparisons between marine regions. The proposed map will aim to answer the following two primary questions: 1. What published evidence exists for the effects of marine man-made structures while in place on the marine ecosystem? 2. What published evidence exists for the effects of the decommissioning of marine man-made structures on the marine ecosystem? The map will follow the Collaboration for Environmental Evidence Guidelines and Standards for Evidence Synthesis in Environmental Management. Searches will be run primarily in English in at least 13 databases and 4 websites. Returns will be screened at title/abstract level and at full-text against pre-defined criteria. Relevant meta-data will be extracted for each study included. Results will be used to build a database of evidence, which will be made freely available. This map, expected to be large, will improve our knowledge of the available evidence for the ecosystem effects of MMS in the global marine environment. It will subsequently inform the production of multiple systematic-reviews and meta-analyses.

Replication forks that are stalled at obstacles on the DNA template can be restarted by homologous recombination. Here, the authors show replication dynamics during homologous recombination-dependent replication fork restart by combining polymerase usage sequencing and a Monte Carlo mathematical model.

We have proposed an impact assessment methodology for determining sustainability in energy-intensive industrial production based on a comprehensive combination of economic, environmental, and social indicators for sustainable development. The goal of this study was to disclose this methodology for assessing sustainability in energy-intensive industrial production. We proved that any energy-intensive chemical, metallurgical, and energy generation processes should maximize the material output values and product value addition to ensure innovative sustainable development. We proposed indicators that determine the levels of increasing the sustainability of energy-intensive production as a whole, as well as taking into account individual technological processes. We proposed a procedure for making managerial decisions to increase the sustainability of energy-intensive outputs using the technological renewal of fixed assets and/or technological modernization of production. Our proposed methodology is based on a graphical model of the technological development’s life cycle of the existing energy-intensive production process. In addition, the proposed methodology ensures resource- and energy-efficiency intensification, together with the environmental safety of the technological processes.

Butyl lactate is a green solvent produced from renewable materials through the reaction of ammonium lactate with n-butanol. It could be a source material for valuable products such as propylene glycol, acrylic acid, its derivatives, and the cyclic monomer of polylactic acid (PLA)—lactate. In this study, we present novel non-catalytic interactions of ammonium lactate and n-butanol carried out in the temperature range of 130–170 °C in a closed system. The study focused on the kinetic modelling of the reaction between ammonium lactate and n-butanol to derive a mathematical model for the reactor unit of butyl lactate synthesis. The aim of this work was to study the kinetics of the interaction between ammonium lactate and n-butanol, as well as to obtain a kinetic model of the process and its parameters. We suggested the chemical transformation routes and determined the kinetic model and parameters that adequately describe the process in a closed system within the studied condition range. The study proposes the first kinetic model that accounts for lactamide formation through two routes. This study showed that the high-temperature non-catalytic interaction of ammonium lactate and n-butanol could be one of the prospective synthesis routes.

We investigated the operation of an axial-flow cyclone as the most promising dust-cleaning equipment based on energy consumption. Numerical solutions were obtained for the gas-solids suspension flow equations in axial flow cyclones with different separation chambers’ geometry using FlowVision software. The chamber’s geometrical features determined the nature of the gas-solids suspension flow, directly affecting the dusty gases’ purification degree. The circulating gas flows and the turbulent “trace” after the swirl generator were found to negatively influence the cyclone efficiency and the hydraulic resistance values. A high chamber height also negatively affected the gas purification since the bulk of dust particles were removed from the gas-solids flow at the initial section. The initial section’s length coincided with the gas-solids suspension’s jet flow zone due to the flow coming off the swirl vanes’ edges. Due to turbulent mixing, the particles’ secondary entrainment and return to the gas flow began to manifest outside this zone. Based on this analysis, it is possible to develop recommendations for choosing the chamber’s geometric parameters, minimizing the influence of the indicated factors. On the basis of this research, it will be possible to ensure cyclones’ high efficiency with significantly lower hydraulic resistance when designing axial-flow cyclones relative to other types of cyclone.

We describe the R package acebayes and demonstrate its use to find Bayesian optimal experimental designs. A decision-theoretic approach is adopted, with the optimal design maximizing an expected utility. Finding Bayesian optimal designs for realistic problems is challenging, as the expected utility is typically intractable and the design space may be high-dimensional. The package implements the approximate coordinate exchange algorithm to optimize (an approximation to) the expected utility via a sequence of conditional one-dimensional optimization steps. At each step, a Gaussian process regression model is used to approximate, and subsequently optimize, the expected utility as the function of a single design coordinate (the value taken by one controllable variable for one run of the experiment). In addition to functions for bespoke design problems with user-defined utility functions, acebayes provides functions tailored to finding designs for common generalized linear and nonlinear models. The package provides a step-change in the complexity of problems that can be addressed, enabling designs to be found for much larger numbers of variables and runs than previously possible. We provide tutorials on the application of the methodology for four illustrative examples of varying complexity where designs are found for the goals of parameter estimation, model selection and prediction. These examples demonstrate previously unseen functionality of acebayes.