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BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity. RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity. CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

We examined the associations of cognitive skills, math-related emotions and beliefs, and gender with responses to an arithmetic fluency intervention. Elementary school children with dysfluent arithmetic skills (N=69) participated in an arithmetic fluency intervention (with and without self-efficacy support) implemented in small groups in schools for 12 weeks. Hierarchical regression models including cognitive skills or math-related emotions and beliefs predicted 21% to 50% of the variation in the intervention response, i.e., improvement in arithmetic fluency. Cognitive skills were associated with the response mainly among boys, whereas math-related emotions and beliefs explained more among girls. Thus, both cognitive and non-cognitive factors and their interaction with gender should be considered when identifying non-responders who may need more individually tailored support at school.

Purpose: This paper investigates how academic teachers engage in identity work and make sense of entrepreneurship and academia in an entrepreneurship training programme. Design/methodology/approach: By employing a sensemaking approach, the paper inductively analyses materials from a business idea development camp organised for academic teachers. Findings: In collective sensemaking during the camp, non-academic facilitators strongly influenced the reflection-in-experience via normative ideas of entrepreneurship and their othering of entrepreneurship from academic work. In their post-camp individual essays, the academic teachers reflect-on-experience and draw parallels between entrepreneurship and academic work constructing sameness. Research limitations/implications: Longitudinal research is needed in identity work and sensemaking among academic teachers in relation to entrepreneurship. Practical implications: Universities need to offer arenas for teachers and other faculty to support identity work and sensemaking. Originality/value: This study generates new understanding of how academic teachers engage in identity work and make sense of entrepreneurship in training when interacting with others. It underscores the importance of time needed for reflection-on-action.

Over the past 2 decades, scholars in various educational contexts have examined Bandura's theorizing about how self-efficacy develops. Bandura proposed 4 primary informational sources of self-efficacy--enactive experiences, vicarious experiences, social persuasions, and physiological and affective states--each of which can be supported in different ways. This article first defines and situates self-efficacy and these sources within a broader social cognitive theoretical frame. Subsequent sections highlight specific ways that educators can apply insights from Bandura's theorizing and from the empirical literature that has examined self-efficacy development at different stages of learning and in diverse contexts. We address how educators can create instructional tasks that show progress, establish supportive social structures, and work with students' emotions in ways that foster self-efficacy. Special attention is given to the sociocultural factors that affect how learners evaluate efficacy-relevant information. Several directions for further applying Bandura's theory are offered.

Self-regulatory efficacy (SRE) among elementary school children is of interest because pupils' self-regulation capacities and SRE influence in managing learning situations. This study investigated variations in the four sources of SRE and how these variations were related to SRE, reading skills and arithmetic skills. The participants were 1284 pupils in Grades 2 to 5. SRE and the sources of SRE were explored via questionnaires completed by the pupils. Latent profile analysis was used to search for subgroups with similar combinations of sources. Five distinguishable and informative profile groups emerged with differences in SRE levels and basic academic skills. The greatest variations were in mastery experiences and emotional states, which were the most sensitive sources for detecting interindividual differences in the domain of self-regulation. Multiple positive sources contributed to higher SRE, while low exposure to sources was related to both lower SRE and low basic academic skills.

Background Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.Methods Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.Results We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.Conclusions Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

ABSTRACT Eutrophication increases the input of labile, algae-derived, organic matter (OM) into lake sediments. This potentially increases methane (CH4) emissions from sediment to water through increased methane production rates and decreased methane oxidation efficiency in sediments. However, the effect of OM lability on the structure of methane oxidizing (methanotrophic) and methane producing (methanogenic) microbial communities in lake sediments is still understudied. We studied the vertical profiles of the sediment and porewater geochemistry and the microbial communities (16S rRNA gene amplicon sequencing) at five profundal stations of an oligo-mesotrophic, boreal lake (Lake Pääjärvi, Finland), varying in surface sediment OM sources (assessed via sediment C:N ratio). Porewater profiles of methane, dissolved inorganic carbon (DIC), acetate, iron, and sulfur suggested that sites with more autochthonous OM showed higher overall OM lability, which increased remineralization rates, leading to increased electron acceptor (EA) consumption and methane emissions from sediment to water. When OM lability increased, the abundance of anaerobic nitrite-reducing methanotrophs (Candidatus Methylomirabilis) relative to aerobic methanotrophs (Methylococcales) in the methane oxidation layer of sediment surface decreased, suggesting that Methylococcales were more competitive than Ca. Methylomirabilis under decreasing redox conditions and increasing methane availability due to their more diverse metabolism (fermentation and anaerobic respiration) and lower affinity for methane. Furthermore, when OM lability increased, the abundance of methanotrophic community in the sediment surface layer, especially Ca. Methylomirabilis, relative to the methanogenic community decreased. We conclude that increasing input of labile OM, subsequently affecting the redox zonation of sediments, significantly modifies the methane producing and consuming microbial community of lake sediments. Importance Lakes are important natural emitters of the greenhouse gas methane (CH4). It has been shown that eutrophication, via increasing the input of labile organic matter (OM) into lake sediments and subsequently affecting the redox conditions, increases methane emissions from lake sediments through increased sediment methane production rates and decreased methane oxidation efficiency. However, the effect of organic matter lability on the structure of the methane-related microbial communities of lake sediments is not known. In this study, we show that, besides the activity, also the structure of lake sediment methane producing and consuming microbial community is significantly affected by changes in the sediment organic matter lability.

The authors study an interesting phenomena of shape coexistence in 186Pb. In an elegant and well-documented experiment, they confirm the coexistence of the three 0+ states in the 186Pb nucleus and reassign the shapes associated with the excited 0+ states.

Abstract Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used 16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life.

Emotional reactivity (e.g. explosive outbursts, tantrums) is a common but understudied challenge for individuals with autism spectrum disorder. Prior research has relied primarily on questionnaire data or observations of very young children. The current study coded emotional reactivity and recovery during a series of standardized frustration tasks in a sample of psychiatrically hospitalized youth with autism spectrum disorder (N = 150; mean age: 12.76) inclusive of the full spectrum of intellectual and functional abilities and explored relationships between emotional reactivity and participant characteristics. The amount, intensity, and duration of negative affect and total range of affect significantly increased from a baseline period to frustration tasks and significantly decreased during recovery. Younger children displayed more negative affect overall; however, age did not moderate change in affect from baseline to frustration tasks or recovery. Adaptive functioning and verbal ability both moderated change in affect, with individuals with lower adaptive functioning and minimally verbal individuals displaying greater reactivity and less recovery. Reactivity was unrelated to non-verbal IQ, overall autism symptom severity, and parent-reported psychiatric/behavioral problems. The results highlight the feasibility and importance of examining emotional reactivity in more severely affected individuals and suggest the need to develop more targeted interventions for emotional reactivity in this group.

The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.

Reliable luminal estrogen receptor (ERα+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ERα expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.

The characteristics of dynamic recrystallization (DRX) of a CoCrFeMnNi high–entropy alloy (HEA) was investigated via hot compression testing in the temperature range 950–1100 °C and at true strain rates of 10−2 and 10−1 s−1. The discontinuous DRX was found to be the dominant mechanism corroborating the microstructural evolution. The progress of the initiation of DRX was investigated in terms of critical strain/stress required using the Poliak–Jonas analytical criterion. Consequently, a new kinetic model based on Avrami–type function was established for the HEA to predict the DRX fractional recrystallization. It was revealed that the volume fraction of DRX grains increased with increasing strain. In the case of 10−2 s−1, steady–state flow was achieved after the completion of one DRX process cycle resulting in further straining, leading to the occurrence of dynamic restoration processes involving formation of substructures and generation and annihilation of dislocations inside the DRX grains which effectively increased the fraction of partially deformed DRX (substructured) grains. A good agreement between the proposed DRX kinetics model and microstructure observation results validated the accuracy of DRX kinetics model for CoCrFeMnNi HEA. The preferred orientation of the non–recrystallized grains was towards the formation of fiber texture, whereas a random micro–texture is revealed in the recrystallized grains.

AA7075 alloy is a high-strength aluminum alloy with properties enhanced by heat treatments. However, like most high-strength aluminum alloys, AA7075 is non-weldable, as it suffers from hot cracking when it is welded or additively manufactured with fusion techniques. A proposed way to reduce the hot cracking tendency is by refining the microstructure by adding nucleation enhancers. In this study, AA7075 powder feedstock was functionalized with 1.7 and 3.4 vol% TiC nanoparticles, printed with laser-directed energy deposition (DED), subjected to T6 heat treatment, and characterized with optical and electron microscopy, electron backscatter diffraction (EBSD), and hardness measurements. Although TiC was not homogeneously distributed in the aluminum matrix, the addition of TiC successfully suppressed hot cracking by inhibiting dendritic growth produced by increased and more uniform nucleation, which resulted in refined equiaxed grains, and thus enhanced the printability of the material.

Abstract Background Finnish community pharmacies have undergone digitalization during the past decade. The introduction of the electronic prescription has had a significant impact on pharmacy workflows, such as the dispensing process. This inevitably has significant sociotechnical implications. We examine the impact of digitalization on the dispensing process and the sociotechnical orientation of a pharmacy. Methods We utilize data collected in customer service situations in Finnish community pharmacies at two points in time: in the traditional workflow, when electronic prescriptions were not in use, and in the new direct dispensing workflow, which is the usual delivery model in the case of electronic prescriptions. We analyze this data in terms of changes in workflow efficiency. We also draw on existing literature to build a conceptual model for digitalization in the pharmacy sector from a sociotechnical standpoint. Results In the Finnish environment, the results, based on our study sample, show that with electronic prescriptions and the direct dispensing model, the delivery time for a single medication over the counter was reduced by 13%. The results also indicate that the process has become more predictable, as the variation in terms of the workflow lead time has decreased. Conclusions The results indicate that the dispensing process has become more efficient in terms of time and throughput as well as more technically oriented and predictable. From a sociotechnical perspective, the results indicate that the technical subsystem has strengthened, and pharmacies have adapted to the new technology in the dispensing process.

Measurement(s) carbon dioxide • methane • dissolved organic carbon • iron(2+) • iron(3+) • total phosphorous • Nitrate Measurement • sulfate • nitrite • ammonium • dissolved nitrogen atom in water • specific ultraviolet absorbance SUVA254 • spectral slope S289 • freshness index BIX • humification index HIX • fluorescence index FI • hydrogen to carbon ratio • oxygen to carbon ratio • m/z Technology Type(s) gas chromatography • total organic carbon analyzer • spectrophotometer • ion chromatography • total nitrogen analyzer • spectrofluorimeter • high-resolution mass spectrometry Factor Type(s) sampling site Sample Characteristic - Organism fungal sp. Sample Characteristic - Environment permafrost • pond water • sediment surface Sample Characteristic - Location Siberia • Sweden • Region of Northern Quebec • State of Alaska • Greenland Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14896713

Measurement(s) Metagenome Technology Type(s) DNA sequencing Factor Type(s) lake Sample Characteristic - Environment lake with an anoxic hypolimnion • freshwater biome Sample Characteristic - Location Sweden • Finland • Canada • Switzerland • Commonwealth of Puerto Rico Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14191043

This article explores the sentiment dynamics present in narratives and their contribution to literary appreciation. Specifically, we investigate whether a certain type of sentiment development in a literary narrative correlates with its quality as perceived by a large number of readers. While we do not expect a story's sentiment arc to relate directly to readers' appreciation, we focus on its internal coherence as measured by its sentiment arc's level of fractality as a potential predictor of literary quality. To measure the arcs' fractality we use the Hurst exponent, a popular measure of fractal patterns that reflects the predictability or self-similarity of a time series. We apply this measure to the fairy tales of H.C. Andersen, using GoodReads' scores to approximate their level of appreciation. Based on our results we suggest that there might be an optimal balance between predictability and surprise in a sentiment arcs' structure that contributes to the perceived quality of a narrative text.

Despite significant advances in autism research, experts have noted that children severely affected by autism spectrum disorder (ASD) appear to have been understudied. Rigorous analysis of this observation has been limited, and the representation of severity has not been well-described. We assessed three domains of severity (communication ability, cognitive functioning, and adaptive functioning) in 367 treatment studies of children with ASD published 1991-2013. We found that the proportion of studies that included the severely affected population decreased significantly over time, as well as wide variability in measurement and reporting. Inadequate representation of the full autism spectrum in the literature could lead to an unbalanced picture of ASD and leave behind those with arguably the greatest need.

We investigated the specificity of reading self-efficacy among second- to fifth-grade children in Finland (N = 1,327). Bandura (1997) theorized that efficacy beliefs can be assessed at different levels of specificity; however, empirical support for this view is scarce among young children. Efficacy beliefs targeting reading-related activities were assessed at three specificity levels (general, intermediate, and specific). Confirmatory factor analysis revealed that these specificity levels are separable, but correlated, and the structure was invariant across gender and grade level. Self-efficacy factors were positively associated with reading fluency, but the strength of these associations varied according to specificity level. Findings suggest that reading self-efficacy in primary grades can and should be assessed at different specificity levels according to research aims.

We examined the relationship between sleep duration and awakenings to Aberrant Behavior Checklist-Community (ABC-C) and Autism Diagnostic Observation Schedule (ADOS-2) scores in hospitalized youth with ASD and behavioral disturbance. Participants included 106 patients with a stay of at least 10 nights. Sleep in the hospital was recorded by staff observation. Higher scores on the ABC-C (irritability, stereotypy, and hyperactivity subscales) at admission were significantly associated with fewer minutes slept during the last five nights of hospitalization. There was no association between total awakenings and ABC-C scores or ADOS-2 comparison scores. Improved understanding of the relationship between sleep quality and maladaptive behavior in this challenging cohort of patients with ASD is vital to the definition and design of future effective interventions.

Tässä artikkelissa tarkastelemme korkeakoulujen opiskelijavalinnoissa käytössä olevia ensikertalaiskiintiöitä. Kiintiöt ovat positiivisen erityiskohtelun muoto, jonka tavoitteena on parantaa jonkin tietyn ryhmän asemaa. Niiden asettamista voidaan tarkastella osana koulutuksen tasa-arvoa ja yhdenvertaisuutta. Kiintiöitä ei Suomessa juuri ole opiskelijavalinnoissa ollut, mutta vuodesta 2016 lähtien otettiin käyttöön ensikertalaisille suunnatut kiintiöt. Pääosa opiskelupaikoista on nykyisin suunnattu ensimmäistä korkeakoulupaikkaansa tavoitteleville. Artikkelissa tarkastelemme, miten ensikertalaisuutta hakijakategoriana määritettiin ja kuinka kiintiöt oikeutettiin. Empiirisenä aineistona olemme analysoineet kiintiöiden asettamiseen liittyneet kaksi lakiesitystä sekä niihin annetut lausunnot. Analyysin perusteella ensikertalaisten suosimiselle löytyi moraalinen oikeutus, mutta samalla kiintiöihin suhtauduttiin myös kriittisesti. Ensikertalaisen kategoria ei yksiselitteisesti rakennu korkeakoulutukseen pääsyn kannalta huonommassa asemassa olevaksi ryhmäksi, sillä yksilöt ovat taustansa vuoksi erilaisissa asemissa. Johtopäätöksemme on, että ensikertalaiskiintiö on kömpelö väline edistämään korkeakoulutuksen oikeudenmukaisuutta, sillä se ei tunnista korkeakoulutuksen hierarkioita, yhteiskunnallisia eroja ja niitä erilaisia positioita, joita ensikertalaisten ja ei-ensikertalaisten kategorioihin asetetuilla hakijoilla on.

Models describing the constitutive flow behaviour of a metallic material are desired for appropriate process design and realization of defect-free components. In this study, constitutive equations based on the hyperbolic-sinusoidal Arrhenius-type model have been developed to define the hot deformation characteristics of a CoCrFeMnNi high-entropy alloy. The experimental true stress-true strain data were generated over a wide temperature (1023–1423 K) and strain rates (10−3–10 s−1) ranges. The impact of strain rate and temperature on deformation behaviour was further characterized through a temperature compensated strain rate parameter, i.e. Zener-Hollomon parameter. Additionally, a mathematical relation was employed to express the influence of various material constants on true-strain ranging from 0.2 to 0.75. Typical third order polynomial relations were found to be appropriate to fit the true-strain dependency of these material constants. The accuracy of the developed constitutive equations was evaluated by using the average absolute relative error (AARE) and correlation coefficient (R); the obtained values were 7.63% and 0.9858, respectively, suggesting reasonable predictions. These results demonstrate that the developed constitutive equations can predict the flow stress behaviour of the alloy with a good accuracy over a wide range of temperature and strain rate conditions and for large strains.

Abstract Scientists have warned decision‐makers about the severe consequences of the global environmental crisis since the 1970s. Yet ecological degradation continues and little has been done to address climate change. We investigated early‐career conservation researchers' (ECR) perspectives on, and prioritization of, actions furthering sustainability. We conducted a survey (n = 67) and an interactive workshop (n = 35) for ECR attendees of the 5th European Congress of Conservation Biology (2018). Building on these data and discussions, we identified ongoing and forthcoming advances in conservation science. These include increased transdisciplinarity, science communication, advocacy in conservation, and adoption of a transformation‐oriented social–ecological systems approach to research. The respondents and participants had diverse perspectives on how to achieve sustainability. Reformist actions were emphasized as paving the way for more radical changes in the economic system and societal values linked to the environment and inequality. Our findings suggest that achieving sustainability requires a strategy that (1) incorporates the multiplicity of people's views, (2) places a greater value on nature, and (3) encourages systemic transformation across political, social, educational, and economic realms on multiple levels. We introduce a framework for ECRs to inspire their research and practice within conservation science to achieve real change in protecting biological diversity.