IT University of Copenhagen

Lampreys are early jawless vertebrates that are the key to understanding the evolution of vertebrates. However, the lack of cytomic studies on multiple lamprey organs has hindered progress in this field. Therefore, the present study constructed a comprehensive cell atlas comprising 604,460 cells/nuclei and 70 cell types from 14 lamprey tissue samples. Comparison of cellular evolution across species revealed that most lamprey cell types are homologous to those in jawed vertebrates. We discovered acinar- and islet-like cell populations despite the lack of parenchymal organs in lampreys, providing evidence of pancreatic function in vertebrates. Furthermore, we investigated the heterogeneity of lamprey immune cell populations. Natterin was highly expressed in granulocytes, and NATTERIN was localized to the lipid droplets. Moreover, we developed a transgenic mouse model expressing Natterin to elucidate the role of NATTERIN in lipid metabolism, whereas the browning of white adipose tissue was induced. These findings elucidate vertebrate cellular evolution and advance our understanding of adipose tissue plasticity and metabolic regulation in lampreys.

Thousands of plants, fungi, and lichen species are traded every year. Although sustainable use is critical for livelihoods and biodiversity conservation, insufficient data prevent detailed sustainability assessments for most species. How can the sustainability of trade in such data‐deficient species be enhanced? We considered a country‐level example of 300 medicinal and aromatic plant, fungus, and lichen species traded in tens of thousands of tons worth tens of millions of US dollars in and from Nepal annually. Past interventions have not ensured sustainable trade, leaving species vulnerable to commercial harvesting and threatening rural household incomes, the processing industry, and government revenues. Building on documented evidence and stakeholder involvement, we used a theory of change approach to develop a sustainable management approach. We produced a draft plan (roadmap) by combining interventions proposed at annual key stakeholder dialogue meetings with recommendations extracted from a literature review on the trade and conservation of commercial medicinal and aromatic plants, fungi, and lichens in Nepal. The draft roadmap was discussed at a national workshop with sector‐wide stakeholder representation to derive the final roadmap. The literature review showed the 41 causal assumptions and theoretical explanations for actions and outcomes. Feedback mechanisms included 6 bundles of mutually reinforcing actions, such as the relationship between increased cultivation and decreased wild harvesting. The roadmap has 5 pathways: increase cultivation, strengthen local management, support domestic businesses, improve sector governance, and increase international collaboration. Each pathway is associated with 2–5 actions (e.g., hand over high‐elevation areas to local communities) that lead to outputs (2‐5) (e.g., an increased area under local management) and outcomes (2‐6) (e.g., less overharvesting). Accordingly, the roadmap offers stakeholders a structured approach to implement future activities and investments to enhance sustainable trade. The approach can be replicated for other countries and products.

The atmospheric concentration of carbon dioxide (CO2) has fluctuated throughout Earth's history. However, the role of CO2 in prebiotic chemistry has been predominantly and limitedly postulated as a C1 precursor, which can be reduced to carbon monoxide or methane mimicking the Wood‐Ljungdahl pathway. Herein we present neglected roles of CO2 as an active promoter in accessing biologically important C3‐builidng blocks such as lactate, via redox‐economic reaction cycles starting from cyanide (C1) and acetaldehyde (C2). We verified that Lewis acidic CO2 facilitates the formation of cyanohydrin of acetaldehyde under ambient conditions. Furthermore, selective protection of cyanohydrin to carbonate by atmospheric CO2 led to anchimeric assisted hydrolysis of the nitrile group to generate lactate. This work supports both warm pond and hydrothermal vent hypotheses, postulating that a CO2‐rich primordial atmosphere and the acidic aqueous solution could have fostered the emergence of biologically relevant molecules and life itself.

The timely deployment of intervention by the rapid response team is crucial to patient safety. Even short delays in response are associated with increased patient risk. Several studies have shown that patients who fulfill rapid response team call criteria but do not receive the intervention for >15 min have an increased risk of death. Such data support the importance of rapid identification and deployment of treatment and imply that the rapid response system is a lifesaving intervention.

pH remains the most important chemical parameter and must be monitored for positive outcomes in areas as different as cheese making and in vitro fertilisation (IVF). Where blood gas analysers enable patient monitoring, starter cultures in cheese manufacturing are still monitored using conventional pH electrodes. Here, we present a homogeneous multiwell plate sensor for monitoring pH, with the same sensitivity as a pH electrode. The homogenous sensor operates in small liquid samples and uses two components: a pH responsive triangulenium dye on a polystyrene nanoparticle, and a freely diffusing commercial reference dye. Sensor measurements were made in triplicate to investigate and document the performance and robustness of the individual components, before we moved on to investigate the multiwell plate sensor design. The pH sensor was first tested in cuvettes, before moving to microwells and smaller volumes. The target is to monitor pH in IVF cultures, and the sensor proved to be operational in the pH range found in in vitro fertilisation buffers, but the references dye was shown not to be suitable for sensors. We conclude that the homogeneous sensor design is sound, but reaching the required precision of ΔpH = 0.01 can only be done with a different reference dye.

INTRODUCTION Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease‐modifying treatments call for more widely applicable biomarkers. METHODS Plasma samples (n = 250) from two mixed memory clinic were included. Participants were divided into amyloid beta positives (Aβ+) and Aβ negatives (Aβ−). Plasma phosphorylated tau (p‐tau) 181, p‐tau231, Aβ1‐42 (Aβ42), Aβ40, Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured by single molecule array. RESULTS Significant differences were found among cognitively unimpaired, mild cognitive impairment, Alzheimer's disease (AD), and non‐AD, and nearly all of the biomarkers were able to predict amyloid status. When combining p‐tau181 and p‐tau231 they predicted Aβ positivity with an area under the curve (AUC) of 0.75, and when combining all biomarkers an AUC of 0.86 was found. DISCUSSION This study supports previous findings on plasma biomarkers, even when investigated in a typical clinical setting in a consecutive, heterogeneous, mixed memory clinic. Highlights This study investigated seven plasma biomarkers in a mixed memory clinic, regardless of amyloid co‐pathology or atypical phenotypes. These findings support previous promising results on plasma biomarkers, even when investigated in a heterogeneous population. The combination of phosphorylated tau (p‐tau)181 and p‐231 performed only slightly worse than a panel of multiple biomarkers, aligning with previous studies. Plasma biomarkers show potential for future applications in primary care, treatment monitoring, and trial selection.

There is limited knowledge on diffusing capacity in scoliosis patients. It remains to be determined if impaired pulmonary diffusing capacity is mostly influenced by reduced alveolar–capillary membrane diffusing capacity (DM, CO), reduced pulmonary capillary blood volume (VC) or both. This study aims to report findings from dual test gas pulmonary diffusing capacity for carbon monoxide and nitric oxide (DL, CO, NO) with quantification of pulmonary diffusing capacity for carbon monoxide corrected for haemoglobin with a five s breath‐hold (DL, COc, 5s) and nitric oxide with a five s breath‐hold (DL, NO, 5s), DM, CO and VC. The study included 57 patients with idiopathic scoliosis seen at our department from 1972 to 1983, all of whom underwent radiological assessment and measurement of DL, CO, NO during examination 40 years after diagnosis. One‐way ANOVA was performed for between‐group differences and Pearson's correlation coefficient was used to assess correlations between DL, CO, NO metrics and Cobb angle. No significant between‐group differences based on disease severity were detected. Thirty‐nine percent of the patients were presented with either reduced DL, COc, 5s or reduced DL, NO, 5s represented as Z‐scores below −1.65. No significant correlations between Cobb angle and Z‐scores for DL, COc, 5s, DL, NO, 5s, DM, CO and VC according to height measurements were found. When using arm span instead, a weak negative correlation between DL, COc, 5s and Cobb angle (r = −0.29; P = 0.04) was detected. In conclusion, approximately 39% of patients with idiopathic scoliosis had either reduced DL, COc, 5s or reduced DL, NO, 5s 40 years after diagnosis with varying contributions from VC or DM, CO.

Background Association between dietary factors and the risk of developing inflammatory bowel disease (IBD) has been studied extensively. However, identification of deleterious dietary patterns merits further study. Aim To investigate the risk of developing Crohn's disease (CD) and ulcerative colitis (UC) according to the inflammatory score of the diet (ISD) in the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods We used validated food frequency questionnaires collected at baseline to compute ISD scores. We estimated the association between ISD score and risks of CD and UC risks using Cox models stratified by centre, sex and age. We adjusted for smoking status, BMI, physical activity, energy intake, educational level and alcohol intake. Results We included 394,255 individuals including 184 incident cases of CD and 459 of UC after median follow‐up of 13.6 years (4,889,910 person‐years). High ISD scores were associated with a higher risk of CD (fourth vs. first quartile‐adjusted HR: 1.88, 95% CI: 1.14–3.10; p‐trend < 0.01) but not of UC (adjusted HR: 0.85, 95% CI: 0.63–1.15; p‐trend 0.21). For CD, this association was mainly observed for women (adjusted HR: 2.14, 95% CI: 1.17–3.91; p‐trend < 0.01). On subgroup analyses, those differences were mainly driven by low intakes of fibre, mono‐unsaturated fatty acids, vitamin C, magnesium, onion and alcohol. Conclusions A high ISD score is associated with a higher risk of developing CD but not UC. These results should be taken into account in high‐risk populations.

DNA‐stabilized silver nanoclusters (DNA‐AgN) are atomically precise and sequence‐tuned nanomaterials with potential applications for deep tissue biomedical imaging. Here, a dual‐emissive DNA‐AgN is presented with fluorescence in the first near‐infrared (NIR‐I) spectral window and microsecond‐lived photoluminescence in the second near‐infrared (NIR‐II) spectral window. High‐resolution electrospray ionization mass spectrometry showed that the emitter has the molecular formula (DNA)2[Ag17]¹¹⁺. The crystallization of (DNA)2[Ag17]¹¹⁺ was unsuccessful, which prevented the use of X‐ray diffraction to determine its structure. However, sequence variations of the templating DNA oligomer provided insights into nucleobases that are critical for stabilizing the Ag17¹¹⁺. Moreover, addition of an adenosine or thymidine at the 5′‐end of the stabilizing DNA strand maintained the composition and photophysical properties of the (DNA)2[Ag17]¹¹⁺, suggesting a potential site for conjugation with biomolecules to enable targeted labeling in future bioimaging applications.

Background Insensitive parenting and ineffective disciplinary strategies are known risk factors for child externalizing behavior. The Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) has documented effect in promoting sensitive parenting, but little is known on how VIPP-SD is experienced by parents. This study explores how parents of preschool children with externalizing behaviors experience change following VIPP-SD delivered by trained childcare providers. Methods Individual qualitative semi-structured interviews were conducted with 9 mothers and 2 fathers to explore the parents’ experiences of change following the intervention. Data were analyzed using Braun and Clarke’s reflexive thematic analysis. Results Four themes were generated: 1) “All of her behavior is actually just a result of how she feels, right?”—Enhanced parental understanding, 2) Meeting the child’s needs in comfort and in play, 3) Learning to prevent and manage conflicts is essential–diverse experiences of gains and progress, 4) “I’m actually not a bad parent”–new positive perspectives. Conclusion Parents experienced an enhanced capacity to understand their child and positive development in their parenting behavior, skills and confidence as well as improvements in the parent-child relationship after receiving VIPP-SD. Findings also suggest potential areas for adaptation of VIPP-SD when intervening in families with a child exhibiting externalizing behaviors, as parental experiences of gains related to conflict management varied. Further research on this matter is recommended.

A protective effect of childhood vaccinations on leukemia risk, particularly acute lymphoblastic leukemia (ALL), has been hypothesized, though findings are inconsistent. We used a nationwide cohort of Danish children born 1997–2018 (n = 1,360,230), to examine associations between childhood vaccinations and leukemia (<20 years) using registry data (follow‐up: December 31, 2018). Cox proportional hazard models with age as the underlying time estimated hazard ratios (HRs) for leukemia (any, ALL, acute myeloid [AML], and other), comparing vaccinated with unvaccinated children. We also accessed the effect of each additional vaccine dose. During 14,536,819 person‐years, 771 children were diagnosed with leukemia (74% ALL, 16% AML, and 10% other). Any vaccination was associated with an increased HR for ALL (HR: 2.76; 95% CI: 0.66–11.58), compared to unvaccinated children, with a change in HR of 1.01 (95% CI: 0.96–1.05) per dose. The corresponding HRs for any leukemia, AML, and other leukemia were 1.04 (95% CI: 0.50–2.17), 0.67 (95% CI: 0.18–2.59) and 0.29 (95% CI: 0.09–0.99), with a change in HR of 0.97 (95% CI: 0.94–1.02), 0.92 (95% CI: 0.84–1.00, p = .062) and 0.88 (95% CI: 0.78–1.00, p = .044) per dose. No significant associations were found for vaccination types, except for the pneumococcal vaccine which was associated with a decreased risk of other leukemia (HR: 0.32; 95% CI: 0.14–0.74). In six‐months lag analyses, no significant associations were observed, and decreased risks were attenuated. The results provide no strong evidence that childhood vaccinations reduce leukemia risk. The limited number of unvaccinated cases and wide confidence intervals suggest cautious interpretation of some findings.

Background The role of carbohydrates in diabetes risk is of particular interest due to conflicting results. This study aims to examine the prospective association between types of dietary carbohydrates (fiber, starch, total sugar, glucose, fructose, lactose, maltose, and added sugar) and the risk of diabetes. Further, this study examines the cross-sectional associations between these nutrients and cardiometabolic risk factors. Methods Danish Health Examination Survey (2007–2008) investigated 76,484 Danes in a representative sample using online questionnaires. Dietary information using a food frequency questionnaire was obtained from 42,836 participants. Information on incident cases of diabetes was obtained from the Danish National Diabetes Register. Cox proportional hazard models were used to estimate Hazard Ratios (95% CI). Multiple linear regression analyses were used to assess the associations between carbohydrate types and cardiometabolic risk factors measured in a subsample of 12,977 participants. Results During a median follow-up of 4.9 years, 970 participants developed diabetes. A higher consumption of fructose, but a lower consumption of glucose was associated with a lower risk of diabetes. In subgroup analyses, these associations were only significant among individuals with other risk factors, such as older age, obesity, low fiber consumption, sedentary behavior, smoking status, and hypertension. Participants with a higher intake of fiber tend to have a lower risk of diabetes and healthier anthropometric parameters compared to those with a lower intake. Conclusions Our findings suggest that a higher intake of dietary fiber and fructose is associated with a lower risk of diabetes and healthier metabolic status, while higher glucose intake is associated with a higher diabetes risk. Graphical Abstract

Amyloid fibrils are highly stable misfolded protein assemblies that play an important role in several neurodegenerative and systemic diseases. Although structural information of the amyloid state is now abundant, mechanistic details about the misfolding process remain elusive. Inspired by the Φ-value analysis of protein folding, we combined experiments and molecular simulations to resolve amino-acid contacts and determine the structure of the transition-state ensemble—the rate-limiting step—for fibril elongation of PI3K-SH3 amyloid fibrils. The ensemble was validated experimentally by Tanford β analysis and computationally by free energy calculations. Although protein folding proceeds on funnel-shaped landscapes, here we find that the energy landscape for the misfolding reaction consists of a large ‘golf course’ region, defined by a single energy barrier and transition state, accessing a sharply funnelled region. Thus, misfolding occurs by rare, successful monomer–fibril end collisions interspersed by numerous unsuccessful binding attempts. Taken together, these insights provide a quantitative and highly resolved description of a protein misfolding reaction.