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Abstract Background Randomized controlled trials (RCTs) are rigorous scientific research designs for evaluating intervention effectiveness. However, implementing RCTs in a real-world context is challenging. To develop strategies to improve its application, it is essential to understand the strengths and challenges of this design. This study thus aimed to explore the strengths, challenges, and strategies for improving the implementation of a pragmatic multicenter, prospective, two-arm RCT evaluating the effects of the Personalized Citizen Assistance for Social Participation (Accompagnement-citoyen Personnalisé d’Intégration Communautaire: APIC; weekly 3-h personalized stimulation sessions given by a trained volunteer over a 12-month period) on older adults’ health, social participation, and life satisfaction. Methods A multiple case study was conducted with 14 participants, comprising one research assistant, seven coordinators, and six managers of six community organizations serving older adults, who implemented the APIC in the context of a RCT. Between 2017 and 2023, qualitative data were extracted from 24 group meetings, seven semi-directed interviews, emails exchanged with the research team, and one follow-up document. Results Aged between 30 and 60 (median ± SIQR: 44.0 ± 6.3), most participants were women from organizations already offering social participation interventions for older adults and working with the public sector. Reported strengths of this RCT were its relevance in assessing an innovative intervention to support healthy aging, and the sharing of common goals, expertise, and strategies with community organizations. Challenges included difficulties recruiting older adults, resistance to potential control group assignments, design complexity, and efforts to mobilize and engage volunteers. The COVID-19 pandemic lockdown and health measures exacerbated challenges related to recruiting older adults and mobilizing volunteers and complicated delivery of the intervention. The strategies that mostly overcame difficulties in recruiting older adults were reducing sample size, simplifying recruitment procedures, emphasizing the health follow-up, extending partnerships, and recognizing and supporting volunteers better. Because of the lockdown and physical distancing measures, the intervention was also adapted for remote delivery, including via telephone or videoconferencing. Conclusion Knowledge of the strengths and challenges of pragmatic RCTs can contribute to the development of strategies to facilitate implementation studies and better evaluate health and social participation interventions delivered under real-life conditions. Trial registration NCT03161860; Pre-results. Registered on May 22, 2017.

Leather is a well-known material with a wide range of applications in clothing, footwear, protection, accessories and furnishing. Further on it is reported in only a few triboelectric series tables, as a material which has an intensive tendency to become positive. In the hereby study, its triboelectric potentials are examined to be used as part of a triboelectric generator which would be part of clothing. Natural leather from cows and sheep was used. Samples of 25 cm2 area were cut and examined together with Polytetrafluoroethylene (PTFE) material, using a prototype measuring triboelectric generator device under a force of 0.5 N. The highest Vpp values were given by the front (grain) side of cow and sheep thin samples, reaching a mean Vpp of 1293 and 1233 mV respectively. In all the tests, the front side of the samples performed better than their back (flesh) as a triboelectric surface. Additionally, the thin samples performed better than the thick ones and the less stiff samples performed better than the stiff ones. The outcoming voltages seem promising in comparison to other ordinary natural materials previously studied. The results point to the potential of leather usage in wearable triboelectric generators.

Cannabis is cultivated for therapeutic and recreational purposes where delta-9 tetrahydrocannabinol (THC) is a main target for its therapeutic effects. As the global cannabis industry and research into cannabinoids expands, more efficient and cost-effective analysis methods for determining cannabinoid concentrations will be beneficial to increase efficiencies and maximize productivity. The utilization of machine learning tools to develop near-infrared (NIR) spectroscopy-based prediction models, which have been validated from accurate and sensitive chemical analysis, such as gas chromatography (GC) or liquid chromatography mass spectroscopy (LCMS), is essential. Previous research on cannabinoid prediction models targeted decarboxylated cannabinoids, such as THC, rather than the naturally occurring precursor, tetrahydrocannabinolic acid (THCA), and utilize finely ground cannabis inflorescence. The current study focuses on building prediction models for THCA concentrations in whole cannabis inflorescences prior to harvest, by employing non-destructive screening techniques so cultivators may rapidly characterize high-performing cultivars for chemotype in real time, thus facilitating targeted optimization of crossbreeding efforts. Using NIR spectroscopy and LCMS to create prediction models we can differentiate between high-THCA and even ratio classes with 100% prediction accuracy. We have also developed prediction models for THCA concentration with a R2 = 0.78 with a prediction error average of 13%. This study demonstrates the viability of a portable handheld NIR device to predict THCA concentrations on whole cannabis samples before harvest, allowing the evaluation of cannabinoid profiles to be made earlier, therefore increasing high-throughput and rapid capabilities.

Several studies have evidenced that children in out-of-home care (OOHC), including foster family care and residential care, reveal high levels of mental health disorders (ranging from 40% to 88%). This study examines the outcomes in mental health reported by key residential workers in a group of children and youth (N = 492) between 8-17 years old who were in residential child care (RCC) in Spain. The research also aims to explore the relationship between mental health outcomes and the provision of mental health services (i.e., receiving any mental health treatment) as well as the influence of child, family, and placement factors. The design of this study includes two measures: a baseline (T1) and a follow-up two years later (T2). The results indicated that 29.9% of young people enjoyed sustained mental health; 26% meaningful improvement in their mental health; 23.5% meaningful deterioration; and the remaining 20.5% showed no meaningful change. One of the main findings was that receiving mental health treatment had a significant impact on mental health outcomes. It is crucial to establish protocols and systematic detection tools to assess mental health and ensure detection and referral to proper treatment.

Today, bridging precision agriculture (PA) with farm management is a high priority. To respond to this challenge, a precision fertilization service for extended crops, namely ‘PreFer’ (developed by 'Ecodevelopment' enterprise), was embedded as a new module in a cloud-based farm management information system (FMIS), namely ‘ifarma’ (developed by 'Agrostis' enterprise). The new PreFer module preserves the full potential of the original service methodology, while taking advantage of all fundamental functionalities of the ifarma platform. PreFer as a service uses a GIS to store and process the farmers’ geodatabases, which are fed from multiple sources, such as soil surveys, satellite data, yield monitors, etc. This GIS is also used to feed the machine learning algorithms of ‘PreFer’ with the required data to produce the prescription maps for both broadcasting and topdressing fertilizations. Then, all tables and maps are transferred from the GIS to the platform upon their production, thus becoming immediately available to the farmers. The ‘ifarma/PreFer' module was tested during the 2022 cultivation season, showing that fully meets farmers' requirements. This work also indicates that synergies like this are more than necessary to create added-value in commercial precision agriculture.

Amy Lewis,1 Despoina Douka,1 Angeliki Koukoura,1 Vasiliki Valla,1 Amie Smirthwaite,2 Susanne Holm Faarbaek,3 Efstathios Vassiliadis1 1Evnia, Copenhagen, Denmark; 2RQM+, Nottingham, England; 3BK Medical, Herlev, DenmarkCorrespondence: Amy Lewis, Email amle@evnia.dkAbstract: Preference testing is a valuable source of information that can be provided by both healthcare professionals (HCPs) and patients (users). It can be used to improve the design and development of medical devices by feeding into device usability and, ultimately, risk management. Furthermore, it can aid with selecting the most appropriate clinical endpoints to be used in the clinical evaluation of a device and increase patient engagement by incorporating patient-relevant outcomes. Preference testing is widely conducted in the food industry but is not widespread in the medical field due to limited guidelines and a lack of regulatory framework. As such, manufacturers may be unaware of the benefits of preference testing and fail to take full advantage of it, or conversely, may use inappropriate methodology and/or analyses and consequently fail to collect meaningful data. In this position paper, we aim to highlight the benefits and uses of preference testing, along with potential methods that could be used for preference testing of medical devices. A key step towards the wider implementation of preference testing in medical devices is for the publication of international standards and guidelines for the collection, assessment, and implementation of preference data into the life cycle of a medical device.Keywords: preference testing, medical device, PPI, patient preference

Humic substances are naturally occurring materials composed of complex biogenic mixtures of substituted aromatic and aliphatic hydrocarbon core materials derived from the degradation and decomposition of dead plant and animal matter. They are ubiquitous in both terrestrial and aquatic systems constituting biotic pools and are characterized by unique properties; they are amphiphilic redox compounds with exceptional chelating features. Humic substances play a crucial role in both agriculture and the environment as carbon sequestrators, soil improvers, plant health promoters, as well as stabilizers of soil aggregates and regulators of organic/inorganic nutrients bioavailability. This review article attempts to summarize current knowledge about the molecular nature and characterization techniques employed for the study of humic substances worldwide as the chemistry of their components differs markedly and depends on natural processes, several abiotic and biotic factors, the origin of the organic matter, and their complexation with inorganic, e.g., metal-ion, compounds. This work is equally concerned with the association of humic substances with dyes, a notorious pollutant, responsible for various environmental issues generally arising from the discharge of untreated effluents into soils and water bodies. Azo dyes, in particular, negatively affect soil microbial communities, as well as plant germination and growth. The aim is to feature the potential contribution of humic substances as novel materials for environment-friendly and sustainable processes.

The Internet of Things (IoT) is considered a promising realm of innovation and revenue generation for the forthcoming years, revolutionizing the way we interact with objects, other people and the world. With an unprecedented but realistic target of trillions of interconnected devices, the IoT calls for technological innovations that lie in the heart of rapid, low-energy and user-friendly communication between people and things. In this respect, the Near Field Communication (NFC) protocol offers advanced efficiency and applicability with low energy consumption, ease of use, flexibility, and increased payload. NFC tags may be embedded in everyday objects, including clothing and apparel, offering an immersive user experience. Wearable NFC antennas and NFC tags embedded in clothing have been presented in the past; nonetheless, in this paper we present, to the best of our knowledge, the first reported development of a NFC antenna on leather substrate. The proposed antenna is sewn using stainless steel thread and operates at the 13.56 MHz frequency range. It may be used alongside with NFC tags in leather apparel like clothing, shoes, accessories, etc., thus extending the possible use cases and applications of the NFC technology and offering an all the more immersive experience for the end user.

Profitability is not given the necessary attention in contemporary precision agriculture. In this work, a new tool, namely ProFit, is developed within a pre-existing farm management system, namely ifarma, to assess the profitability of precision agriculture applications in extended crops, as most of the current solutions available on the market respond inadequately to this need. ProFit offers an easy-to-use interface to enter financial records, while it uses the dynamic map view environment of ifarma to display the profitability maps. Worked examples reveal that profitability maps end up being quite different from yield maps in site-specific applications. The module is regulated at a 5 m spatial resolution, thus allowing scaling up of original and processed data on a zone-, field-, cultivar-, and farm-scale. A bottom-up approach, taking advantage of the full functionality of ifarma, together with a flexible architecture allowing future interventions and improvements, renders ProFit an innovative commercial tool.

It is known that Jovian radio and high energy electron emissions are observed near Earth. The question we address in this study is whether the quasi-periodic ~10 h and ~40/15–20 min (QP-10 h, QP-40/15–20 min) energetic particle and magnetic field periodicities observed by Ulysses during its distant encounter with Jupiter in 2003 were also detectable as far as the Earth’s orbit. Surprisingly, we found that at the end of the extreme 2003 Halloween events, during times of a highly disturbed Jovian magnetosphere, as inferred from strong bKOM radio emissions observed by Ulysses, and a magnetic connection of Earth with the Jovian magnetosphere, as suggested by simulation results of the interplanetary magnetic field (IMF), the ACE satellite observed, between at least 25–27 November 2013 at the Lagrangian Point L1 (LPL1), all the characteristic Jovian periodicities. In particular, by using high-time resolution data (1/5 min), we found, for the first time, quasi-permanent electron, and magnetic field QP-10/5 h, QP-40 min and QP-15/20 data variations at LPL1 for at least three days. These observations reasonably suggest that low energy (~50–~300 keV) Jovian electrons reached the Earth’s environment; the observations examined extend the lowest energy limit of the Jovian electron spectrum from 200 keV to ~50 keV. In addition, the ACE satellite observed an impressive series of QP-10/5 h energetic (≤0.05 MeV) ion bursts (EIBs) with strong cross-field intensity gradients at the onset/decay phase of the events and energy-dependent field aligned anisotropy suggesting ion streaming in the anti-sunward direction during their main phase. A comparison of simultaneously obtained measurements by ACE at the LPL1 and by Geotail upstream from the bow shock and in the magnetosphere suggests that the QP-10/5 h EIBs are inconsistent with the concept of a terrestrial origin. On the contrary, the observations indicate that the series of QP-10/5 h EIBs on 25–27 November 2003 was a spatial effect caused by the ~10/5 h quasi-periodic approach of a large-scale sheet to the Earth’s environment. The source of the ion population forming the QP-10/5 h sharp EIBs seems most probably Jovian ions accumulated in the interplanetary space, although a solar ion contribution is possible. Based on the above results, it is reasonable to suggest that the observed QP-10 h, QP-40 min and QP-15/20 periodicities are due to Jovian influence. Further research is needed to study the cause of the QP-10/5 h EIBs. This study presents new data which extend our view on the influence of the QP-10 h/QP-40/QP-15/20 min Jovian emissions from the outer to the inner heliosphere at 1 AU.

Introduction: Eyelid reconstruction can be performed by primary closure, a graft of different lamellae, and local and/or regional flaps, single or combined. This reconstruction becomes more complex when the upper and lower eyelids are resected to total thickness, and the eyeball is preserved. The objective is to report the techniques used for periorbital reconstruction in bipalpebral resection cases (upper and lower) with preservation of the eyeball by the Group of Orthopalpebral Surgery of the Division of Plastic Surgery and Burns of HCFMUSP. Methods: All cases that met the inclusion criteria from 2000 to 2019 were reviewed, and epidemiological, surgical, and postoperative follow-up data were described. Results: Only two cases were submitted to total exeresis of the periorbital tissue and remained susceptible to eyeball preservation. Both were reconstructed with frontal flaps with complete occlusion of the eyeball at the first moment, followed by the release in stages, keeping the globe viable after reconstruction completion. Discussion: Similar reports are scarce in the literature, and, in these cases, surgical results were functionally acceptable but with significant aesthetic limitations. Conclusion: We suggest a new option for total reconstruction of the upper and lower eyelid (with a single pedicular flap, devoid of connective graft and in multiple stages) that protects and conserves the eyeball during the various stages of surgery. The results were functionally favorable, considering the severity of the cases.

Summary: Reward timing, that is, the delay after which reward is delivered following an action is known to strongly influence reinforcement learning. Here, we asked if reward timing could also modulate how people learn and consolidate new motor skills. In 60 healthy participants, we found that delaying reward delivery by a few seconds influenced motor learning. Indeed, training with a short reward delay (1 s) induced continuous improvements in performance, whereas a long reward delay (6 s) led to initially high learning rates that were followed by an early plateau in the learning curve and a lower performance at the end of training. Participants who learned the skill with a long reward delay also exhibited reduced overnight memory consolidation. Overall, our data show that reward timing affects the dynamics and consolidation of motor learning, a finding that could be exploited in future rehabilitation programs.

Schizosaccharomyces pombe is a model unicellular eukaryote with ties to the basic research, oenology and industrial biotechnology sectors. While most investigations into S. pombe cell biology utilize Leupold’s 972h- laboratory strain background, recent studies have described a wealth of genetic and phenotypic diversity within wild populations of S. pombe including stress resistance phenotypes which may be of interest to industry. Here we describe the genomic and transcriptomic characterization of Wilmar-P, an S. pombe isolate used for bioethanol production from sugarcane molasses at industrial scale. Novel sequences present in Wilmar-P but not in the laboratory S. pombe genome included multiple coding sequences with near-perfect nucleotide identity to Schizosaccharomyces octosporus sequences. Wilmar-P also contained a ∼100kb duplication in the right arm of chromosome III, a region harboring ght5+, the predominant hexose transporter encoding gene. Transcriptomic analysis of Wilmar-P grown in molasses revealed strong downregulation of core environmental stress response genes and upregulation of hexose transporters and drug efflux pumps compared to laboratory S. pombe. Finally, examination of the regulatory network of Scr1, which is involved in the regulation of several genes differentially expressed on molasses, revealed expanded binding of this transcription factor in Wilmar-P compared to laboratory S. pombe in the molasses condition. Together our results point to both genomic plasticity and transcriptomic adaptation as mechanisms driving phenotypic adaptation of Wilmar-P to the molasses environment and therefore adds to our understanding of genetic diversity within industrial fission yeast strains and the capacity of this strain for commercial scale bioethanol production.

Cannabis is commercially cultivated for both therapeutic and recreational purposes in a growing number of jurisdictions. The main cannabinoids of interest are cannabidiol (CBD) and delta-9 tetrahydrocannabidiol (THC), which have applications in different therapeutic treatments. The rapid, nondestructive determination of cannabinoid levels has been achieved using near-infrared (NIR) spectroscopy coupled to high-quality compound reference data provided by liquid chromatography. However, most of the literature describes prediction models for the decarboxylated cannabinoids, e.g., THC and CBD, rather than naturally occurring analogues, tetrahydrocannabidiolic acid (THCA) and cannabidiolic acid (CBDA). The accurate prediction of these acidic cannabinoids has important implications for quality control for cultivators, manufacturers and regulatory bodies. Using high-quality liquid chromatography–mass spectroscopy (LCMS) data and NIR spectra data, we developed statistical models including principal component analysis (PCA) for data quality control, partial least squares regression (PLS-R) models to predict cannabinoid concentrations for 14 different cannabinoids and partial least squares discriminant analysis (PLS-DA) models to characterise cannabis samples into high-CBDA, high-THCA and even-ratio classes. This analysis employed two spectrometers, a scientific grade benchtop instrument (Bruker MPA II–Multi-Purpose FT-NIR Analyzer) and a handheld instrument (VIAVI MicroNIR Onsite-W). While the models from the benchtop instrument were generally more robust (99.4–100% accuracy prediction), the handheld device also performed well (83.1–100% accuracy prediction) with the added benefits of portability and speed. In addition, two cannabis inflorescence preparation methods were evaluated: finely ground and coarsely ground. The models generated from coarsely ground cannabis provided comparable predictions to that of the finely ground but represent significant timesaving in terms of sample preparation. This study demonstrates that a portable NIR handheld device paired with LCMS quantitative data can provide accurate cannabinoid predictions and potentially be of use for the rapid, high-throughput, nondestructive screening of cannabis material.

Perennial ryegrass (Lolium perenne L.), an economically important pasture and turf grass, is commonly infected with asexual Epichloë species endophytes. Endophytes provide enhanced bioprotection by producing alkaloids, and research often focusses on the negative impact on grazing animals. However, alkaloid distribution throughout the plant and their role in biocontrol of insect pests and diseases are less well understood. Additionally, intermediate compounds have not been investigated for their impacts on animal welfare and biological control in pasture-based scenarios. Here, a single liquid chromatography–mass spectrometry (LC-MS) method was used to measure seven alkaloids in different perennial ryegrass tissues infected with SE or NEA12 endophytes. High alkaloid recoveries and a clear plant matrix effect emphasize the importance of using matrix-matched standards for accurate quantitation. The method is sensitive, detecting alkaloids at low concentrations (nanogram levels), which is important for endophyte strains that produce compounds detrimental to livestock. Concentrations were generally highest in seeds, but distribution differed in the shoots/roots: peramine, terpendole E, terpendole C and lolitrem B were higher in shoots, whilst ergovaline, paxilline and epoxy-janthitrem I were more evenly distributed throughout the two tissues. Knowledge of alkaloid distribution may allow for concentrations to be predicted in roots based on concentrations in the shoots, thereby assisting future determinations of resistance to insects, especially subterranean root-feeding pests.

Companion diagnostics (CDx) hail promise of improving the drug development process and precision medicine. However, there are various challenges involved in the clinical development and regulation of CDx, which are considered high-risk in vitro diagnostic medical devices given the role they play in therapeutic decision-making and the complications they may introduce with respect to their sensitivity and specificity. The European Union (E.U.) is currently in the process of bringing into effect in vitro Diagnostic Medical Devices Regulation (IVDR). The new Regulation is introducing a wide range of stringent requirements for scientific validity, analytical and clinical performance, as well as on post-market surveillance activities throughout the lifetime of in vitro diagnostics (IVD). Compliance with General Safety and Performance Requirements (GSPRs) adopts a risk-based approach, which is also the case for the new classification system. This changing regulatory framework has an impact on all stakeholders involved in the IVD Industry, including Authorized Representatives, Distributors, Importers, Notified Bodies, and Reference Laboratories and is expected to have a significant effect on the development of new CDx.

Summary: Besides relying heavily on sensory and reinforcement feedback, motor skill learning may also depend on the level of motivation experienced during training. Yet, how motivation by reward modulates motor learning remains unclear. In 90 healthy subjects, we investigated the net effect of motivation by reward on motor learning while controlling for the sensory and reinforcement feedback received by the participants. Reward improved motor skill learning beyond performance-based reinforcement feedback. Importantly, the beneficial effect of reward involved a specific potentiation of reinforcement-related adjustments in motor commands, which concerned primarily the most relevant motor component for task success and persisted on the following day in the absence of reward. We propose that the long-lasting effects of motivation on motor learning may entail a form of associative learning resulting from the repetitive pairing of the reinforcement feedback and reward during training, a mechanism that may be exploited in future rehabilitation protocols.

AimTo investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat.Study designTwo-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.5months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells.ResultsStereological analysis showed that intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied.ConclusionIT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.

Juvenile xanthogranuloma (JXG) is the most common benign tumor of the group of non-Langerhans histiocytic proliferative diseases. Lesions; 2 cm are considered giant JXG, with reports of lesions of up to 18 cm. Oculopalpebral lesions may require surgical treatment to control symptoms. This study reports a case of an 8-year-old boy who had four eyelids and the middle third of the face affected by giant JXG. He underwent three resections, one of which was of great depth that required a full-thickness skin graft directly on the levator palpebrae superioris aponeurosis. Subsequently, three fat-grafting procedures were performed and adequate functional and aesthetic results were achieved without lesion recurrence.

In the last decade, smart textiles have become very popular as a concept and have found use in many applications, such as military, electronics, automotive, and medical ones. In the medical area, smart textiles research is focused more on biomonitoring, telemedicine, rehabilitation, sport medicine or home healthcare systems. In this research, the development and localization accuracy measurements of a smart T-shirt are presented, which will be used by elderly people for indoor localization in ambient assisted living applications. The proposed smart T-shirt and the work presented is considered to be applicable in cases of elderly, toddlers or even adults in indoor environments where their continuous real-time localization is critical. This smart T-shirt integrates a localization sensor, namely the Localino sensor, together with a solar panel for energy harvesting when the user is moving outdoors, as well as a battery/power bank that is both connected to the solar panel and the Localino sensor for charging and power supply respectively. Moreover, a mock-up house was deployed, where the Localino platform anchors were deployed at strategic points within the house area. Localino sensor nodes were installed in all the house rooms, from which we obtained the localization accuracy measurements. Furthermore, the localization accuracy was also measured for a selected number of mobile user scenarios, in order to assess the platform accuracy in both static and mobile user cases. Details about the implementation of the T-shirt, the selection and integration of the electronics parts, and the mock-up house, as well as about the localization accuracy measurements results are presented in the paper.

The author compares two types of Orthodox ecclesiology. The first one is the eucharistic/liturgical ecclesiology based on the biblical (Semitic) understanding of the Church as God’s people, gathered around Christ and called to proclaim the coming Kingdom every time the Church comes together ἐπὶ τὸ αὐτό (in one place), especially for celebrating the Eucharist. The second is the therapeutic/cathartic ecclesiology associated with the theological school of Alexandria. This type considers the Church not as the image of eschaton but rather as the image of the beginning of all being, the image of creation. In this ecclesiology, the Church is viewed separately from the historically existing church community, as a perfect and eternal Idea. The emphasis is put on the purification of the soul (catharsis), deliverance from passions and healing (therapy) of the fallen human nature. The spirituality and mission of the Church within the second type of ecclesiology are aimed not at the synergistic and prophetic proclamation of the Kingdom of God but at the salvation of the soul of each particular Christian. According to the author, today the Church needs to return to the prophetic nature of Orthodoxy as well as to the fundamental biblical tradition.

There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.

Abstract Background Optimal glucose metabolism is central to the growth and development of cells. In microbial eukaryotes, carbon catabolite repression (CCR) mediates the preferential utilization of glucose, primarily by repressing alternate carbon source utilization. In fission yeast, CCR is mediated by transcriptional repressors Scr1 and the Tup/Ssn6 complex, with the Rst2 transcription factor important for activation of gluconeogenesis and sexual differentiation genes upon derepression. Through genetic and genome-wide methods, this study aimed to comprehensively characterize CCR in fission yeast by identifying the genes and biological processes that are regulated by Scr1, Tup/Ssn6 and Rst2, the core CCR machinery. Results The transcriptional response of fission yeast to glucose-sufficient or glucose-deficient growth conditions in wild type and CCR mutant cells was determined by RNA-seq and ChIP-seq. Scr1 was found to regulate genes involved in carbon metabolism, hexose uptake, gluconeogenesis and the TCA cycle. Surprisingly, a role for Scr1 in the suppression of sexual differentiation was also identified, as homothallic scr1 deletion mutants showed ectopic meiosis in carbon and nitrogen rich conditions. ChIP-seq characterised the targets of Tup/Ssn6 and Rst2 identifying regulatory roles within and independent of CCR. Finally, a subset of genes bound by all three factors was identified, implying that regulation of certain loci may be modulated in a competitive fashion between the Scr1, Tup/Ssn6 repressors and the Rst2 activator. Conclusions By identifying the genes directly and indirectly regulated by Scr1, Tup/Ssn6 and Rst2, this study comprehensively defined the gene regulatory networks of CCR in fission yeast and revealed the transcriptional complexities governing this system.