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Abstract Background Confidence in childhood vaccination is high in Norway and the Norwegian Childhood Immunization Programme (NCIP) achieves high overall coverage rates. However, lower coverage has been observed for some immigrant groups, including Polish immigrants who represent the largest immigrant group in Norway. Anti-vaccine sentiments and increased refusal of mandatory childhood vaccination has been on the rise in Poland, but it is unknown whether such attitudes also apply to Polish immigrants in Norway, as they experience a different vaccination policy and perhaps also different attitudes to vaccines. This qualitative study aims to explore attitudes towards childhood vaccination in Norway among Polish immigrants. Methods We interviewed 15 Polish parents living in Norway in 2022. We recruited the participants by purposive sampling and analyzed the interviews by reflexive thematic analysis. Results Three themes were identified: views of childhood vaccination, vaccine hesitancy, and differences in childhood vaccination between Poland and Norway. Overall, the participants favored childhood vaccination and viewed most of the vaccines included in the NCIP as safe and reliable. Human papilloma virus, meningococcal and pneumococcal vaccines were declined by some of the parents. Comparisons of childhood vaccination in Poland and Norway was evident in many of the interviews, especially among parents whose children had received vaccines in both countries. The participants were well acquainted with the NCIP, favored voluntary childhood vaccination, and the majority expressed a high level of trust in Norwegian health authorities. Conclusions Polish immigrants to Norway generally expressed positive views about childhood vaccination. Non-vaccination was related to lack of knowledge and/or unfamiliarity with certain vaccines and not with anti-vaccine sentiments or conspiracy theories. The study highlights how parents’ knowledge, in combination with norms and trends from both birth country and country of residence, influence parents’ decision making about vaccination.

Maternal vaccination against pertussis is safe and provides effective protection against pertussis for the newborn, but the vaccine coverage rate remains generally low. Norway is currently planning for introduction of routine maternal pertussis vaccination. To assess maternal pertussis vaccination acceptance among pregnant Norwegian women, we surveyed women at 20–40 weeks gestation in 2019. Among the 1,148 pregnant women participating in this cross-sectional study, 73.8% reported they would accept pertussis vaccination during pregnancy if it was recommended, 6.9% would not accept and 19.2% were undecided. Predictors for low likelihood of accepting pertussis vaccination during pregnancy included low confidence in health authorities and in maternal pertussis vaccination safety and effectiveness, low awareness and adherence to influenza vaccination during pregnancy, and low awareness of pertussis vaccination. The major reasons reported for not accepting or being undecided about maternal pertussis vaccination were lack of information on vaccine safety for both mother and child. Most women reported that they would consult their general practitioner or a midwife for information if they were offered maternal pertussis vaccination. General practitioners and midwives were also regarded as the most trustworthy sources of information if the women were in doubt about accepting vaccination. We conclude that information addressing safety concerns and raising awareness about maternal pertussis vaccination could increase acceptance of maternal pertussis vaccination. Our findings highlight the pivotal role of the antenatal and primary health care services in providing such information to pregnant women.

Abstract The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA DM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA NT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA DM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPA DM AML. Elevated CEBPA levels, driven by CEBPA NT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA DM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

Abstract Single-cell resolution analysis of complex biological tissues is fundamental to capture cell-state heterogeneity and distinct cellular signaling patterns that remain obscured with population-based techniques. The limited amount of material encapsulated in a single cell however, raises significant technical challenges to molecular profiling. Due to extensive optimization efforts, single-cell proteomics by Mass Spectrometry (scp-MS) has emerged as a powerful tool to facilitate proteome profiling from ultra-low amounts of input, although further development is needed to realize its full potential. To this end, we carry out comprehensive analysis of orbitrap-based data-independent acquisition (DIA) for limited material proteomics. Notably, we find a fundamental difference between optimal DIA methods for high- and low-load samples. We further improve our low-input DIA method by relying on high-resolution MS1 quantification, thus enhancing sensitivity by more efficiently utilizing available mass analyzer time. With our ultra-low input tailored DIA method, we are able to accommodate long injection times and high resolution, while keeping the scan cycle time low enough to ensure robust quantification. Finally, we demonstrate the capability of our approach by profiling mouse embryonic stem cell culture conditions, showcasing heterogeneity in global proteomes and highlighting distinct differences in key metabolic enzyme expression in distinct cell subclusters.

IntroductionProinflammatory cytokines are implicated in pancreatic ß cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of nonsense-mediated RNA decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß cells.MethodsA luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3, or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. The gain- or loss-of-function of two key NMD components, UPF3B and UPF2, is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques.ResultsCyt attenuate NMD activity in insulin-producing cell lines and primary human ß cells. These effects are found to involve ER stress and are associated with the downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing raise or lower Cyt-induced cell death, respectively, in EndoC-ßH3 cells and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increases alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in the extracellular matrix (ECM), including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitizes ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signaling, potentially serving as a protective response against Cyt-induced NMD component expression.ConclusionOur findings highlight the central importance of RNA turnover in ß cell responses to inflammatory stress.

Here the authors show that differentiation of haematopoietic stem cells into mature blood cells is primed by cell type-specific transcription factors at the enhancer level during early differentiation, before they confere promoter-driven growth arrest, and activate post-mitotic terminal differentiation.

High and equitable COVID-19 vaccination coverage is important for pandemic control and prevention of health inequity. However, little is known about socioeconomic correlates of booster vaccination coverage. In this cross-sectional study of all Norwegian adults in the national vaccination program (N = 4,190,655), we use individual-level registry data to examine coverage by levels of household income and education of primary (≥2 doses) and booster (≥3 doses) vaccination against COVID-19. We stratify the analyses by age groups with different booster recommendations and report relative risk ratios (RR) for vaccination by 25 August 2022. In the 18–44 y group, individuals with highest vs. lowest education had 94% vs. 79% primary coverage (adjusted RR (adjRR) 1.15, 95%CI 1.14–1.15) and 67% vs. 38% booster coverage (adjRR 1.55, 95% CI 1.55–1.56), while individuals with highest vs. lowest income had 94% vs. 81% primary coverage (adjRR 1.10, 95%CI 1.10–1.10) and 60% vs. 43% booster coverage (adjRR 1.23, 95%CI 1.22–1.24). In the ≥45 y group, individuals with highest vs. lowest education had 96% vs. 92% primary coverage (adjRR 1.02, 95%CI 1.02–1.02) and 88% vs. 80% booster coverage (adjRR 1.09, 95%CI 1.09–1.09), while individuals with highest vs. lowest income had 98% vs. 82% primary coverage (adjRR 1.16, 95%CI 1.16–1.16) and 92% vs. 64% booster coverage (adjRR 1.33, 95%CI 1.33–1.34). In conclusion, we document large socioeconomic inequalities in COVID-19 vaccination coverage, especially for booster vaccination, even though all vaccination was free-of-charge. The results highlight the need to tailor information and to target underserved groups for booster vaccination.

Genetic susceptibility loci for oropharyngeal cancer have been reported but these studies have not always examined human papillomavirus (HPV) status. Here, the authors perform genome-wide analysis taking into account HPV16 serology status and report two independent loci in the HLA region, suggesting the protective role of HLA variants against HPV infection.

Abstract Background Cervical cancer incidence is influenced by screening and risk factors in the population. The main risk factor for cervical cancer is sexually transmitted human papillomavirus (HPV), which is sexually transmitted and thus associated with sexual behavior. Smoking, parity and hormonal contraceptive use may also be associated with cervical cancer risk. We compared incidence, screening coverage and risk behaviors for cervical cancer between health regions in Norway. Methods We obtained data on incidence of cervical cancer among Norwegian women during 1992–2016 and data on screening coverage from the Cancer Registry of Norway. We obtained data on sexual behavior and smoking from a population-based survey of 16,575 Norwegian women who were 18–45 years old in 2005. Results Cervical cancer incidence was higher in the northern and southeastern region than in the middle and western region (range in incidence per 100,000 person-years during 1992–2016; north: 10.5 to 14.6; southeast: 9.3 to 12.9; mid: 6.8 to 9.5; west: 8.4 to 10.0). The incidence decreased modestly in the north (average annual percentage change (95% confidence interval) − 1.0 (− 1.2 to − 0.7)) and southeast (− 0.7 (− 1.0 to − 0.3)), but did not change significantly in the mid (− 0.3 (− 1.0 to 0.4)) and west (− 0.3 (− 0.6 to 0.0)). Compared to the national average, women in the north had earlier sexual debut, more partners and higher prevalence of ever having had a sexually transmitted infection (STI), while the opposite was observed among women in the west. Women in the middle and southeastern regions tended to be similar to the national average for sexual behaviors. Although less pronounced, the prevalence of smoking showed regional patterns similar to that observed for sexual behaviors, while ever-use of hormonal contraceptives and cervical screening coverage was similar between regions. Conclusions There were regional differences in cervical cancer incidence during the era of nationally organized cervical screening in Norway. To some extent, these differences corresponded to regional differences in risk behavior for cervical cancer in the Norwegian female population.

Single-cell proteomics can provide insights into the molecular basis for cellular heterogeneity. Here, the authors develop a multiplexed single-cell proteomics and computational workflow, and show that their strategy captures the cellular hierarchies in an Acute Myeloid Leukemia culture model.

Prevalence of different HPV genotypes is changing after HPV vaccination. The associated risks are needed for optimizing cervical cancer screening. To estimate HPV type-specific prevalence, odds ratio (OR), and positive predictive value (PPV) for cervical cytological abnormalities, we determined 41 different HPV genotypes in cervical samples from a population-based sample of 8351 women aged 18–51 years before HPV vaccination era (V501-033; NCT01077856). Prevalence of HPV16 was 4.9% (95% CI: 4.4–5.5) with the PPV for high-grade cytology 11.2%, and OR 11.9 (95% CI: 8.5–16.5). Carcinogenic HPVs included in the nonavalent vaccine (HPV16,18,31,33,45,52,58) had a population prevalence of 14.4% (95% CI: 13.5–15.4), with PPV of 8.0% (95% CI: 6.8–9.3) and OR 23.7 (95% CI: 16.0–63.5) for high-grade cytology. HPV types currently included in most screening tests, but not vaccinated against (HPV35,39,51,56,59,66,68) had a joint prevalence of 8.5% (95% CI: 7.8–9.2) with PPV of 4.4% (95% CI: 3.3–5.7) and OR of 2.9 (95% CI: 2.0–4.0) for high-grade cytology. The other 27 non-carcinogenic genotypes had a prevalence of 11.8%, PPV of 2.9% (95% CI:2.1–3.9), and OR 1.5 (95% CI: 1.1–2.2.) for high-grade cytology. These results suggest that HPV screening tests in the post-vaccination era might perform better if restricted to the HPV types in the nonavalent vaccine and screening for all 14 HPV types might result in suboptimal balance of harms and benefits.

Jane Darke’s 1979 article “The Primary Generator and the Design Process” appeared in the very first issue of Design Studies. In the four decades of design research that followed, the article became a classic. In the article’s revaluation of the role subjectivity plays in design, Darke posits a construct called the “the primary generator”—a limited set of (typically subjective) constraints—as a way for architects to engage with design tasks characterized by complexity. The primary generator acts as a random starting point, located within a subset of constraints, which is iteratively adjusted as the design process takes place. It may be construed as a subjectively valued organizing principle driving the design process. It may also be read as either a liberating force of subjective creative freedom, or as a subjective source of bias and fixation that the architect may be unwilling or unable to later escape. Darke herself held both these positions over time. Her ideas on the malleability of the design space and the very initiation of the creative design process by imposition of constraints have been critical in the evolution of constraint research, which represents a rich strand of interdisciplinary design research.

Abstract It is valuable to establish a population‐based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high‐grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high‐grade precancerous cervical lesions (n = 1240) during 2004‐2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0‐86.4) in CIN2, 91.6% (95% CI 89.7‐93.5) in CIN3, and 86.4% (95% CI 83.7‐89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2‐40.6; CIN3: 50.2%, 95% CI 46.8‐53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8‐13.9; CIN3: 12.1%, 95% CI 9.9‐14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9‐52.7 and 15.3%, 95% CI 12.5‐18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P

ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.

Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.

The case presented here was the center of the 11th Design Thinking Research Symposium (DTRS11) and concerns extensive in situ collected video-based data of everyday design team activity traced longitudinally in a professional team of designers working with user involvement. The DTRS11 dataset was shared and analyzed by 28 international design research teams, who approached the data with each their preferred methodology and theoretical interests. In addition to the case description, the current paper also identified themes for distinct analyses conducted by individual design research teams: co-creation, cross-cultural design, design thinking within organizations, and design tools and materials, each of which stem from particulars in the present case, but at the same time serve as hints to developments that are taking place in design practice more broadly. Keywords: Design practice, Design process, Design in organizations, User-centered design, Cross-cultural design, Design tools

Summary: B cell development depends on the coordinated expression and cooperation of several transcription factors. Here we show that the transcription factor ETS-related gene (ERG) is crucial for normal B cell development and that its deletion results in a substantial loss of bone marrow B cell progenitors and peripheral B cells, as well as a skewing of splenic B cell populations. We find that ERG-deficient B lineage cells exhibit an early developmental block at the pre-B cell stage and proliferate less. The cells fail to express the immunoglobulin heavy chain due to inefficient V-to-DJ recombination, and cells that undergo recombination display a strong bias against incorporation of distal V gene segments. Furthermore, antisense transcription at PAX5-activated intergenic repeat (PAIR) elements, located in the distal region of the Igh locus, depends on ERG. These findings show that ERG serves as a critical regulator of B cell development by ensuring efficient and balanced V-to-DJ recombination. : Søndergaard et al. demonstrate that ERG is a critical transcriptional regulator essential for B cell development. Loss of ERG leads to a marked reduction in V-to-DJ recombination at the Igh locus, precluding B cell progenitors from expressing the pre-B cell receptor, which is required for entering the final stages of B cell development. Keywords: ETS-related gene, ERG, B cell development, V(D)J recombination, pre-BCR, immunoglobulin heavy-chain gene, transcriptional control

Since brainstorming was introduced as a technique in 1953 it has been assumed that the best way to produce good ideas is through the production of many ideas, which has later been named the equal-odds rule. However, this finding that productivity often leads to creative quality has rarely been examined in psychometric studies of creative cognition. To close this knowledge gap, we examined the relationship between individual differences in creative personality, as assessed by the personality trait openness to experience, and both the quantity and quality of ideas produced in a divergent thinking task. Across 154 graduate students we found a positive and significant relationship between creative personality and the number of ideas produced, as well as their creative value. The present results indicate that while quantity does breed quality in creative production, the effect is moderated by individual differences, specifically the personality trait Openness to Experience. As the level of Openness to Experience increases, the relation of quantity of ideas to average Creative value gradually becomes positive and significant. We discuss the possible reasons for and implications of our findings.

During transcription, most eukaryotic genes generate multiple alternative cleavage and polyadenylation (APA) sites, leading to the production of transcript isoforms with variable lengths in the 3' untranslated region (3'UTR). In contrast to somatic cells, male germ cells, especially pachytene spermatocytes and round spermatids, express a distinct reservoir of mRNAs with shorter 3'UTRs that are essential for spermatogenesis and male fertility. However, the mechanisms underlying the enrichment of shorter 3'UTR transcripts in the developing male germ cells remain unknown. Here, we report that UPF2-mediated nonsense-mediated mRNA decay (NMD) plays an essential role in male germ cells by eliminating ubiquitous genes-derived, longer 3'UTR transcripts, and that this role is independent of its canonical role in degrading "premature termination codon" (PTC)-containing transcripts in somatic cell lineages. This report provides physiological evidence supporting a noncanonical role of the NMD pathway in achieving global 3'UTR shortening in the male germ cells during spermatogenesis.

Information was gathered on the distribution of white-clawed crayfish Austropotamobius pallipes complex in the watercourses of the Alessandria province (NW Italy), on the biological and ecological preferences of the species, and on the features of the biotopes in which it is found. A total of 409 sites on 361 watercourses connected to the main sub-basins of the Po River were analysed, with data gathered during the field research phase, conducted for three consecutive summers from 2002 through 2004. Thirteen percent of the sites investigated were found to currently house crayfish populations. The persistence in time of superficial water and natural morphology of the watercourse were found to be the chief requirements for the presence of crayfish. Data on land use, human density and other factors which potentially limit the survival of crayfish populations were also analysed.

Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.

Transcription factors are key regulators of hematopoietic stem cells (HSCs) and act through their ability to bind DNA and impact on gene transcription. Their functions are interpreted in the complex landscape of chromatin, but current knowledge on how this is achieved is very limited. C/EBPα is an important transcriptional regulator of hematopoiesis, but its potential functions in HSCs have remained elusive. Here we report that C/EBPα serves to protect adult HSCs from apoptosis and to maintain their quiescent state. Consequently, deletion of Cebpa is associated with loss of self-renewal and HSC exhaustion. By combining gene expression analysis with genome-wide assessment of C/EBPα binding and epigenetic configurations, we show that C/EBPα acts to modulate the epigenetic states of genes belonging to molecular pathways important for HSC function. Moreover, our data suggest that C/EBPα acts as a priming factor at the HSC level where it actively promotes myeloid differentiation and counteracts lymphoid lineage choice. Taken together, our results show that C/EBPα is a key regulator of HSC biology, which influences the epigenetic landscape of HSCs in order to balance different cell fate options.

Moult is the process by which birds replace their feathers. It is a costly process in terms of energy and reduced flight ability but necessary for the maintenance of the plumage and its functions. Because birds generally avoid to moult while engaged with other energy demanding activities such as breeding and migration, the analysis of moult data gives insight into how birds fit this life stage into the annual cycle, on time constraints in the annual cycle, and on the effects of environmental variables on the timing of moult. The analysis of moult data requires non-standard statistical techniques. More than 20~years ago Underhill and Zucchini developed a likelihood approach for estimating duration, mean start date and variation in start date of a population of moulting birds. However, use of these models has been limited, mainly due to the lack of user-friendly software. The moult package for R implements the Underhill-Zucchini models, allowing the user to specify moult models in a regression type formula. In addition the functions allow the moult parameters (duration, and mean and variation in start date) to depend on explanatory variables. We here describe the package, give a brief summary of the theory and illustrate the models on two datasets included in the package.

The influence of day/night conditions on individual animal/plant species has been widely studied, but diel cycle studies of the entire stream macroinvertebrate community are extremely rare. This study explored potential dissimilarities between daytime and nighttime macroinvertebrate assemblages by extensive fieldwork conducted in the Lemme stream, a natural water course of NW Italy. Here numerous structural and functional metrics (richness, abundance, biomass, indicator taxa, composition, biomonitoring values and feeding groups) were evaluated at the family level. Small-scale environmental variables were investigated to understand possible differences between macroinvertebrate assemblages in the daytime/nighttime. After collecting and identifying 21 459 organisms of 50 taxa, Chironomidae (Diptera) was the most abundant under both day and night conditions. Our findings stressed that similar results and biological information on daytime/nighttime data were obtained. No marked differences could be related to various factors: heterotrophic condition of small-order streams, presence of aquatic predators under night and day conditions, absence of taxa with a specific phototaxis. Of all the environmental variables, velocity was always the most important in both situations, with some differences detected in the importance of the second variable (riverbed substrate diameter). This research, and future studies on different conditions and geographic areas, will contribute knowledge on stream macroinvertebrate diel activity, and provide useful information about efficient sampling strategies.

BackgroundTranscription factors play a key role in lineage commitment and differentiation of stem cells into distinct mature cells. In hematopoiesis, they regulate lineage-specific gene expression in a stage-specific manner through various physical and functional interactions with regulatory proteins that are simultanously recruited and activated to ensure timely gene expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is such a factor and is essential for the development of granulocytic/monocytic cells. The activity of C/EBPα is regulated on several levels including gene expression, alternative translation, protein interactions and posttranslational modifications, such as phosphorylation. In particular, the phosphorylation of serine 248 of the transactivation domain has been shown to be of crucial importance for granulocytic differentiation of 32Dcl3 cells in vitro.Methodology/principal findingsHere, we use mouse genetics to investigate the significance of C/EBPα serine 248 in vivo through the construction and analysis of Cebpa(S248A/S248A) knock-in mice. Surprisingly, 8-week old Cebpa(S248A/S248A) mice display normal steady-state hematopoiesis including unaltered development of mature myeloid cells. However, over time some of the animals develop a hematopoietic disorder with accumulation of multipotent, megakaryocytic and erythroid progenitor cells and a mild impairment of differentiation along the granulocytic-monocytic lineage. Furthermore, BM cells from Cebpa(S248A/S248A) animals display a competitive advantage compared to wild type cells in a transplantation assay.Conclusions/significanceTaken together, our data shows that the substitution of C/EBPα serine 248 to alanine favors the selection of the megakaryocytic/erythroid lineage over the monocytic/granulocytic compartment in old mice and suggests that S248 phosphorylation may be required to maintain proper hematopoietic homeostasis in response to changes in the wiring of cellular signalling networks. More broadly, the marked differences between the phenotype of the S248A variant in vivo and in vitro highlight the need to exert caution when extending in vitro phenotypes to the more appropriate in vivo context.

BackgroundNonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues.Methodology/principal findingsHere we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration.Conclusion/significanceCollectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology.

Searching for sources of inspiration is central to creative design; however, we have limited knowledge of individual inspiration search strategies in response to varying levels of task constraints. We studied 39 high-school students' inspiration search strategies using Google Images. Low task constrainedness led to "divergent search" marked by quick iterations, limited design task usage, and a heterogeneous image set. Intermediate constrainedness prompted "in-depth," "on-task exploration" characterized by slow and careful iterations with more search result examination, extensive design task usage, and homogenous images. High constrainedness led to "flexible bracketing" with quick, flexible design task use, ending with heterogeneous images. Images from the intermediately and highly constrained conditions generated more ideas and were perceived as more inspiring (relative to low) in a new group of students. We discuss the idea of a 'sweet spot' of constrainedness in an inspiration search process in design and consider implications for design research and future work.

With the objective to investigate associations between sociodemographic characteristics and participation in interventions designed to increase participation in cervical cancer screening among under‐screened women, we randomized a random sample of 6000 women in Norway aged 35–69 years who had not attended cervical screening for ≥10 years to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self‐sampling kit (opt‐in), or (iii) a self‐sampling kit unsolicited (send‐to‐all). We analyzed how sociodemographic characteristics were associated with screening participation within and between screening arms. In the send‐to‐all arm, increased screening participation ranged from 17.1% (95% confidence interval [95% CI] = 10.3% to 23.8%) to 30.0% (95% CI = 21.5% to 38.6%) between sociodemographic groups. In the opt‐in arm, we observed smaller, and at times, non‐significant increases within the range 0.7% (95% CI = −5.8% to 7.3%) to 19.1% (95% CI = 11.6% to 26.7%). In send‐to‐all versus control comparisons, there was greater increase in participation for women in the workforce versus not (6.1%, 95% CI = 1.6% to 10.6%), with higher versus lower income (7.6%, 95% CI = 2.2% to 13.1%), and with university versus primary education (8.5%, 95% CI = 2.4% to 14.6%). In opt‐in versus control comparisons, there was greater increase in participation for women in the workforce versus not (4.6%, 95% CI = 0.7% to 8.5%), with higher versus lower income (6.3%, 95% CI = 1.5% to 11.1%), but lower increase for Eastern European versus Norwegian background (−12.7%, 95% CI = −19.7% to −5.7%). Self‐sampling increased cervical screening participation across all sociodemographic levels, but inequalities in participation should be considered when introducing self‐sampling, especially with the goal to reach long‐term non‐attending women. [ABSTRACT FROM AUTHOR]