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Abstract Since the introduction of next generation sequencing technologies, the field of epigenomics has evolved rapidly. However, most commonly used assays are enrichment-based methods and thus only semi-quantitative. Nucleosome occupancy and methylome sequencing (NOMe-seq) allows for quantitative inference of chromatin states with single locus resolution, but this requires high sequencing depth and is therefore prohibitively expensive to routinely apply to organisms with large genomes. To overcome this limitation, we introduce guidedNOMe-seq, where we combine NOMe profiling with large scale sgRNA synthesis and Cas9-mediated region-of-interest (ROI) liberation. To facilitate quantitative comparisons between multiple samples, we additionally develop an R package to standardize differential analysis of any type of NOMe-seq data. We extensively benchmark guidedNOMe-seq in a proof-of-concept study, dissecting the interplay of ChAHP and CTCF on chromatin. In summary we present a cost-effective, scalable, and customizable target enrichment extension to the existing NOMe-seq protocol allowing genome-scale quantification of nucleosome occupancy and transcription factor binding at single allele resolution.

Abstract Background Disease-related malnutrition affects a significant number of patients with cancer and poses a major social problem worldwide. Despite both global and national guidelines to prevent and treat malnutrition, the prevalence is high, ranging from 20 to 70% in all patients with cancer. This study aimed to explore the current practice of nutritional support for patients with cancer at a large university hospital in Norway and to explore potential barriers and facilitators of the intervention in the Green Approach to Improved Nutritional support for patients with cancer (GAIN), prior to implementation in a clinical setting. Methods The study used individual interviews and a focus group discussion to collect data. Study participants included different healthcare professionals and patients with cancer treated at a nutrition outpatient clinic. The Consolidated Framework for Implementation Research (CFIR) was used to guide the thematic data analysis. Results Barriers connected to the current nutritional support were limited resources and undefined roles concerning responsibility for providing nutritional support among healthcare professionals. Facilitators included a desire for change regarding the current nutritional practice. The GAIN intervention was perceived as feasible for patients and healthcare professionals. Potential barriers included limited knowledge of technology, lack of motivation among patients, and a potential added burden experienced by the participating patients. Conclusions The identification of the potential barriers and facilitators of the current nutritional support to patients with cancer will be used to plan the implementation of improved nutritional support in a randomized controlled trial for patients with cancer prior to clinical implementation. The current findings may be of value to others trying to implement either or both nutritional support and digital application tools in a clinical healthcare setting. Trial registration The study was registered in the National Institutes of Health Clinical trials 08/09/22. The identification code is NCT05544318.

BackgroundThis study used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), and explored the psychological and social challenges of 14-year-olds who report psychotic symptoms. Research on help-seeking youths indicates comorbid symptoms of depression, anxiety, and social deterioration, but less is known about non-help-seeking individuals who may not use healthcare services, possibly skewing comorbidity profiles. Also, findings suggest that adolescents manifesting psychotic symptoms refrain from pursuing help. This gap underscores the necessity of studying non-help-seeking adolescents to better understand their needs and the risks they face without intervention.MethodsWe analyzed responses from adolescents who completed the 14-year questionnaire in MoBa (N = 127), identifying those as at risk by their high scores on psychosis-risk items, within the top 0.4% (N = 58). Comparative analyses were conducted against matched controls to assess differences in psychological and social functioning (N = 69).ResultsResults indicated that the at-risk adolescents experience significantly more depression and anxiety and have lower self-esteem and poorer social functioning than controls. Social functioning parameters, including leisure activities, social competence, quality of parental relationship, and sense of school belonging, were significantly worse than those observed in controls. The results indicate a pronounced vulnerability among non-help-seeking adolescents at-risk, similar to issues seen in help-seeking youths.ConclusionThese findings highlight the importance of early identification and intervention strategies that reach beyond traditional clinical settings, suggesting the efficacy of population or community-based screenings to prevent long-term adverse outcomes. The study proposes a broader understanding of psychosis risk, stressing the importance of inclusive approaches to support at-risk adolescents effectively.

Abstract Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.

Abstract Background Suicide prevention media campaigns are one way of reaching people at increased suicide risk who would otherwise not seek help. This is the first study of a Norwegian campaign directed both at individuals at risk for suicide and at their social network. Methods We evaluated a media campaign consisting of outdoor posters, feature articles, film clips, and online banners in print, digital, and social media spread across the Mid-Norway region in late autumn 2022. This campaign material consisted of information about how to seek help for suicide thoughts and mental health problems and how to help a friend in similar situations. Before and after this campaign, 1149 adult individuals living in Mid-Norway participated in a survey on attitudes to suicide, mental ill health, and help-seeking. Results There were only marginal changes in attitudes and help-seeking literacy after the campaign. This result was sustained when controlling for age, sex, and campaign visibility. For males, there were a few changes in the negative direction, i.e. lack of willingness to seek help from family and friends, after the campaign. Conclusion We conclude that the campaign did not seem to have the desired effect and suggest ways of improving future regional Norwegian media campaigns.

Internal tides are known to be an important source of mixing in the oceans, especially in the bottom boundary layer. The depth of internal-tide generation therefore seems important for benthic life and the formation of cold-water coral mounds, but internal-tide conversion is generally investigated in a depth-integrated sense. Using both idealized and realistic simulations on continental slopes, we found that the depth of internal-tide generation increases with increasing slope steepness and decreases with intensified shallow stratification. The depth of internal-tide generation also shows a typical latitudinal dependency related to Coriolis effects. Using a global database of cold-water corals, we found that, especially in Northern Hemisphere autumn and winter, the global depth pattern of internal-tide generation correlates (rautumn = 0.70, rwinter = 0.65, p < 0.01) with that of cold-water corals: shallowest near the poles and deepest around the Equator, with a decrease in depth around 25° S and N, and shallower north of the Equator than south. We further found that cold-water corals are situated significantly more often on topography that is steeper than the internal-tide beam (i.e. where supercritical reflection of internal tides occurs) than would be expected from a random distribution: in our study, in 66.9 % of all cases, cold-water corals occurred on a topography that is supercritical to the M2 tide whereas globally only 9.4 % of all topography is supercritical. Our findings underline internal-tide generation and the occurrence of supercritical reflection of internal tides as globally important for cold-water coral growth. The energetic dynamics associated with internal-tide generation and the supercritical reflection of internal tides likely increase the food supply towards the reefs in food-limited winter months. With climate change, stratification is expected to increase. Based on our results, this would decrease the depth of internal-tide generation, possibly creating new suitable habitat for cold-water corals shallower on continental slopes.

IntroductionFor limiting global warming to well below 2°C rapid and stringent GHG emissions reductions are required. In addition, we also need to actively remove CO2 from the atmosphere via carbon dioxide removal (CDR). This will require advances in policymaking and governance to incentivise, coordinate and regulate CDR, including strict monitoring to ensure durable, additional removals that do not compete with emission reduction efforts. While it is critical to learn from the existing evidence on CDR policy and governance, there is no overview of this dispersed body of literature right now. IPCC and other science assessments have therefore treated the subject very selectively. This work addresses this lack of overview by systematically mapping the literature assessing policy and governance dimensions of CDR.MethodsSystematic mapping provides a comprehensive view of a research field by analysing the state of evidence, i.e. how much research is available at any point in time on which topics and geographies studied by whom, when and where. We use an AI-enhanced approach to systematic mapping, trimming down an initial set of about 30,000 documents on CDR to a set of 876 that deal with governance and policy issues.ResultsOur findings show sharply growing attention to CDR policies and governance issues over time, but with limited coverage of the Global South. Long established conventional CDR methods such as afforestation dominate the literatureparticularly in ex-post studies -with little coverage of many novel CDR methods, such as biochar or direct air carbon capture and storage. We observe a shift from an initial discussion on CDR in international agreements towards the planning and implementation phase of national and sub-national policies.DiscussionOur map can help to inform upcoming science assessments with critical information around CDR policies and governance and might serve as a starting point for generating a rigorous knowledge base on the topic in the future.

Objectives: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years. Methods: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days. Results: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%). Conclusions: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age.

Medicine counterfeiting is a worldwide problem affecting all therapeutic areas. The analysis of such products is sometimes a scientific challenge, since their chemical composition is unknown and might be very different from the one of the original product. While some counterfeited drug products are quite easy to detect, others are close in composition with the genuine products. The health consequences of counterfeit medicines are appalling since these products can contain the =rong chemical composition, impurities or toxic compounds, and be manufactured and stored in dreadful conditions that do not even respect the basic hygienic conditions. Providing reliable analytical tools is therefore necessary for an efficient fight against the phenomenon. In this study, the analysis of counterfeits of psychotropic drugs presenting a rare closeness in composition to the genuine drugs will be described. It will be exposed how the choice of reliable analytical strategy and tools is decisive for the correct authentication of such pharmaceuticals. The results of classical methods like High-Performance Liquid Chromatography (HPLC) will be presented. Then the contribution of vibrational spectroscopy and imaging tools, including spectral imaging and Near infrared (NIR) spectroscopy, and spectral imaging, will be described, as well as Gas Chromatography coupled with Mass Spectrometry (GC–MS), 1H Nuclear Magnetic Resonance (NMR), 3D microscopy as support for the physical analysis, and finally X-ray fluorescence spectroscopy (XRF) as an elemental analysis technology. The results of the forensic analysis will also reveal analytical links between the counterfeit cases, providing useful information for law enforcement investigations.

Abstract While basaltic volcanism is dominant during rifting and continental breakup, felsic magmatism may be a significant component of some rift margins. During International Ocean Discovery Program (IODP) Expedition 396 on the continental margin of Norway, a graphite‐garnet‐cordierite bearing dacitic unit (the Mimir dacite) was recovered in two holes within early Eocene sediments on Mimir High (Site U1570), a marginal high on the Vøring Transform Margin. Here, we present a comprehensive textural, petrological, and geochemical study of the Mimir dacite in order to assess its origin and discuss the geodynamic implications. The major mineral phases (garnet, cordierite, quartz, plagioclase, alkali feldspar) are hosted in a fresh rhyolitic, vesicular, glassy matrix that is locally mingled with sediments. The major element chemistry of garnet and cordierite, the presence of zircon inclusions with inherited cores, and thermobarometric calculations all support an upper crustal metapelitic origin. While most magma‐rich margin models favor crustal anatexis in the lower crust, thermobarometric calculations performed here show that the Mimir dacite was produced at upper‐crustal depths (

BackgroundThe diagnosis of inflammatory rheumatic diseases (IRDs) is often delayed due to unspecific symptoms and a shortage of rheumatologists. Digital diagnostic decision support systems (DDSSs) have the potential to expedite diagnosis and help patients navigate the health care system more efficiently. ObjectiveThe aim of this study was to assess the diagnostic accuracy of a mobile artificial intelligence (AI)–based symptom checker (Ada) and a web-based self-referral tool (Rheport) regarding IRDs. MethodsA prospective, multicenter, open-label, crossover randomized controlled trial was conducted with patients newly presenting to 3 rheumatology centers. Participants were randomly assigned to complete a symptom assessment using either Ada or Rheport. The primary outcome was the correct identification of IRDs by the DDSSs, defined as the presence of any IRD in the list of suggested diagnoses by Ada or achieving a prespecified threshold score with Rheport. The gold standard was the diagnosis made by rheumatologists. ResultsA total of 600 patients were included, among whom 214 (35.7%) were diagnosed with an IRD. Most frequent IRD was rheumatoid arthritis with 69 (11.5%) patients. Rheport’s disease suggestion and Ada’s top 1 (D1) and top 5 (D5) disease suggestions demonstrated overall diagnostic accuracies of 52%, 63%, and 58%, respectively, for IRDs. Rheport showed a sensitivity of 62% and a specificity of 47% for IRDs. Ada’s D1 and D5 disease suggestions showed a sensitivity of 52% and 66%, respectively, and a specificity of 68% and 54%, respectively, concerning IRDs. Ada’s diagnostic accuracy regarding individual diagnoses was heterogenous, and Ada performed considerably better in identifying rheumatoid arthritis in comparison to other diagnoses (D1: 42%; D5: 64%). The Cohen κ statistic of Rheport for agreement on any rheumatic disease diagnosis with Ada D1 was 0.15 (95% CI 0.08-0.18) and with Ada D5 was 0.08 (95% CI 0.00-0.16), indicating poor agreement for the presence of any rheumatic disease between the 2 DDSSs. ConclusionsTo our knowledge, this is the largest comparative DDSS trial with actual use of DDSSs by patients. The diagnostic accuracies of both DDSSs for IRDs were not promising in this high-prevalence patient population. DDSSs may lead to a misuse of scarce health care resources. Our results underscore the need for stringent regulation and drastic improvements to ensure the safety and efficacy of DDSSs. Trial RegistrationGerman Register of Clinical Trials DRKS00017642; https://drks.de/search/en/trial/DRKS00017642

The hippocampal-dependent memory system and striatal-dependent memory system modulate reinforcement learning depending on feedback timing in adults, but their contributions during development remain unclear. In a 2-year longitudinal study, 6-to-7-year-old children performed a reinforcement learning task in which they received feedback immediately or with a short delay following their response. Children’s learning was found to be sensitive to feedback timing modulations in their reaction time and inverse temperature parameter, which quantifies value-guided decision-making. They showed longitudinal improvements towards more optimal value-based learning, and their hippocampal volume showed protracted maturation. Better delayed model-derived learning covaried with larger hippocampal volume longitudinally, in line with the adult literature. In contrast, a larger striatal volume in children was associated with both better immediate and delayed model-derived learning longitudinally. These findings show, for the first time, an early hippocampal contribution to the dynamic development of reinforcement learning in middle childhood, with neurally less differentiated and more cooperative memory systems than in adults.

Abstract Since the initial patent in 2001, the Magnetic Particle Imaging community has endeavored to develop a human-applicable Magnetic Particle Imaging scanner, incorporating contributions from various research fields. Here we present an improved head-sized Magnetic Particle Imaging scanner with low power consumption, operated by open-source software and characterize it with an emphasis on human safety. The focus is on the evaluation of the technical components and on phantom experiments for brain perfusion. We achieved 3D single- and multi-contrast imaging at 4 Hz frame rate. The system characterization includes sensitivity, resolution, perfusion and multi-contrast experiments as well as field measurements and sequence analysis. Images were acquired with a clinically approved tracer and within human peripheral nerve stimulation thresholds. This advanced scanner holds potential as a tomographic imager for diagnosing conditions such as ischemic stroke (different stages) or intracranial hemorrhage in environments lacking electromagnetic shielding, such as the intensive care unit.

Framework-forming cold-water corals (CWCs) are ecosystem engineers that build mounds in the deep sea that can be up to several hundred metres high. The effect of the presence of cold-water coral mounds on their surroundings is typically difficult to separate from environmental factors that are not affected by the mounds. We investigated the environmental control on and the importance of ecosystem engineering for cold-water coral reefs using annotated video transect data, spatial variables (MEMs), and hydrodynamic model outputs in a redundancy analysis and with variance partitioning. Using available hydrodynamic simulations with cold-water coral mounds and simulations where the mounds were artificially removed, we investigated the effect of coral mound ecosystem engineering on the spatial configuration of reef habitat and discriminated which environmental factors are and which are not affected by the mounds. We find that downward velocities in winter, related to non-engineered environmental factors, e.g. deep winter mixing and dense-water cascading, cause substantial differences in reef cover at the broadest spatial scale (20–30 km). Such hydrodynamic processes that stimulate the food supply towards the corals in winter seem more important for the reefs than cold-water coral mound engineering or similar hydrodynamic processes in summer. While the ecosystem-engineering effect of cold-water corals is frequently discussed, our results also highlight the importance of non-engineered environmental processes. We further find that, due to the interaction between the coral mound and the water flow, different hydrodynamic zones are found on coral mounds that likely determine the typical benthic zonations of coral rubble at the mound foot, the dead coral framework on the mound flanks, and the living corals near the summit. Moreover, we suggest that a so-called Massenerhebung effect (well known for terrestrial mountains) exists, meaning that benthic zonation depends on the location of the mound rather than on the height above the seafloor or water depth. Our finding that ecosystem engineering determines the configuration of benthic habitats on cold-water coral mounds implies that cold-water corals cannot grow at deeper depths on the mounds to avoid the adverse effects of climate change.

Abstract Controlling chemical processes in live cells is a challenging task. The spatial heterogeneity of biochemical reactions in cells is often overlooked by conventional means of incubating cells with desired chemicals. A comprehensive understanding of spatially diverse biochemical processes requires precise control over molecular activities at the subcellular level. Herein, a closed‐loop optoelectronic control system is developed that allows the manipulation of biomolecular activities in live cells at high spatiotemporal precision. Chemical‐selective fluorescence signals are utilized to command lasers that trigger specific chemical processes or control the activation of photoswitchable inhibitors at desired targets. This technology is fully compatible with laser scanning confocal fluorescence microscopes. The authors demonstrate selective interactions of a 405 nm laser with targeted organelles and simultaneous monitoring of cell responses by fluorescent protein signals. Notably, blue laser interaction with the endoplasmic reticulum leads to a more pronounced reduction in cytosolic green fluorescent protein signals in comparison to that with nuclei and lipid droplets. Moreover, when combined with a photoswitchable inhibitor, microtubule polymerization is selectively inhibited within the subcellular compartments. This technology enables subcellular spatiotemporal optical manipulation over chemical processes and drug activities, exclusively at desired targets, while minimizing undesired effects on non‐targeted locations.

Abstract There is substantial cognitive heterogeneity among patients with schizophrenia (SZ) and bipolar disorders (BD). More knowledge about the magnitude and clinical correlates of performance variability could improve our understanding of cognitive impairments. Using double generalized linear models (DGLMs) we investigated cognitive mean and variability differences between patients with SZ (n = 905) and BD spectrum disorders (n = 522), and healthy controls (HC, n = 1170) on twenty-two variables. The analysis revealed significant case-control differences on 90% of the variables. Compared to HC, patients showed larger intra-individual (within subject) variability across tests and larger inter-individual (between subject) variability in measures of fine-motor speed, mental processing speed, and inhibitory control (SZ and BD), and in verbal learning and memory and intellectual functioning (SZ). In SZ, we found that lager intra -and inter (on inhibitory control and speed functions) individual variability, was associated with lower functioning and more negative symptoms. Inter-individual variability on single measures of memory and intellectual function was additionally associated with disorganized and positive symptoms, and use of antidepressants. In BD, there were no within-subject associations with symptom severity. However, greater inter-individual variability (primarily on inhibitory control and speeded functions) was associated with lower functioning, more negative -and disorganized symptoms, earlier age at onset, longer duration of illness, and increased medication use. These results highlight larger individual differences in patients compared to controls on various cognitive domains. Further investigations of the causes and correlates of individual differences in cognitive function are warranted.

Abstract Gastrointestinal bleeding, as a potentially life-threatening condition, is typically diagnosed by radiation-based imaging modalities like computed tomography or more invasively catheter-based angiography. Endoscopy enables examination of the upper gastrointestinal tract and the colon but not of the entire small bowel. Magnetic Particle Imaging (MPI) enables non-invasive, volumetric imaging without ionizing radiation. The aim of this study was to evaluate the feasibility of detecting gastrointestinal bleeding by single- and multi-contrast MPI using human-sized organs. A 3D-printed small bowel phantom and porcine small bowel specimens were prepared with a defect within the bowel wall as the source of a bleeding. For multi-contrast MPI, the bowel lumen was filled with an intestinal tracer representing an orally administered tracer. MPI was performed to evaluate the fluid exchange between the vascular compartment of the bowel wall and the lumen while a blood pool tracer was applied. Leakage of the blood pool tracer was observed to the bowel lumen. Multi-contrast MPI enabled co-registration of both tracers at the same location within the bowel lumen indicating gastrointestinal bleeding. Single- and multi-contrast MPI are feasible to visualize gastrointestinal bleeding. Therefore, MPI might emerge as a useful tool for radiation-free detection of bleeding within the entire gastrointestinal tract.