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Newtonian mechanics is still among the most difficult topics in the physics' syllabus taught at school. For example, even after completing traditional instruction, students still think that a force is necessary to maintain motion. Therefore, a revised method of instruction is needed that meets students' learning needs. The aim of the project presented in this article was to develop and evaluate novel teaching units for the introduction to Newtonian mechanics. Rather than changing methodology, the content area itself was restructured innovatively with careful consideration of the most common preconceptions. Based on diSessa's notion of conceptual change as the reorganisation of these only loosely connected preconceptions, so-called p-prims (diSessa, 1993, 2008), the strategy pursued was aimed at triggering the activation of appropriate p-prims while avoiding the activation of inappropriate p-prims. For example, to lower the activation priority of the above mentioned notion, a consistent introduction to mechanics via two-dimensional dynamics was chosen. In the first year of the corresponding study, 10 participating teachers taught their 7th-grade classes in the traditional one-dimensional way. In the following year, the same teachers taught (other) 7th-grade classes using the revised twodimensional way. Students' knowledge of mechanics, self-concept and interest in physics were assessed. This quasiexperimental field study showed a significant improvement in students' conceptual understanding. Thus the findings of this project suggest that altering the content structure of a particular topic might be an important parameter to improving learning outcomes.

Electricity has shaped modern civilization in a way few other discoveries have. Nonetheless, few students successfully develop a basic understanding of voltage, current, and resistance or their mutual relationship in simple DC circuits. Despite teachers' best efforts in the classroom, so-called "alternative conceptions" often prevail after traditional instruction. In particular, voltage has proven to be a difficult concept to teach--many students erroneously think of voltage as a property of electric current. Furthermore, a battery is often considered to be a source of constant current rather than constant voltage. In order to help students develop a better understanding of simple DC circuits, we developed a new curriculum with an accompanying computer simulation that illustrates potential differences in circuits in order to make voltage rather than current the students' primary concept when analyzing circuits. To this end, the curriculum takes typical alternative conceptions into account and builds on students' everyday experiences with air pressure in order to provide them with an immediately tangible counterpart in electric potential. In analogy to air pressure differences that cause an air flow, voltage is introduced as an "electric pressure difference" that causes an electric current. Using the accompanying computer simulation, potential differences are visualized in simple DC circuits using color coding and a height representation. The new curriculum including teaching resources as well as the newly developed computer simulation are both freely available online to teachers and students alike.

This article reports the development of a two-tier simple electric circuits test (2T-SEC Test). Simple electric circuits are introduced to students early in their school years and are an important part of the physics curriculum all the way to the university level. However, many students do not develop an adequate conceptual understanding of simple electric circuits and especially of electrical voltage. For this reason, six physics education research groups from Germany and Austria started a large study to evaluate and improve middle-school students' conceptual understanding of simple electric circuits. As a first step, we developed the test instrument presented in this article. First, nine semistructured interviews were conducted with middle-school students in Austria. The interviews were transcribed, analyzed and (common) student difficulties with simple electric circuits were identified. Second, based on the results from the interviews and previous research on this topic, an instrument consisting of 25 two-tier multiple-choice items was developed and administered to N = 1568 middle-school students in Austria and Germany. Third, the data were evaluated using Rasch analysis. The item reliability of the test was 0.99, while the person reliability of paired scoring was 0.62 and the reliability of separate scoring was 0.75. The average difficulties of the main concepts regarding simple electric circuits (open and closed circuits, electric current, resistance, series and parallel circuits, and electrical voltage) were calculated and compared. The analysis suggests that the concept of voltage is most difficult for students while distinguishing between open and closed circuits is the easiest.

[This paper is part of the Focused Collection on Curriculum Development: Theory into Design.] Developing a solid understanding of simple electric circuits represents a major challenge to most students in middle school. In particular, students tend to reason exclusively with current and resistance when analyzing electric circuits as they view voltage as a property of the electric current and not an independent physical quantity. As a result, they often struggle to understand the important relationship between voltage and current in electric circuits. Following diSessa's interpretation of learning as the construction and reorganization of previously loosely connected elements of knowledge ("p-prims") into a coherent mental structure ("coordination class"), a new curriculum was developed that systematically builds on students' everyday experiences with air pressure (e.g., with air mattresses and bicycle tires). In order to make voltage rather than current the students' primary concept when analyzing electric circuits, voltage is introduced as an "electric pressure difference" across a resistor that is as much the cause for an electric current as air pressure differences are the cause for air flow. The objective of the curriculum is to provide a structure for students to develop a qualitative understanding of simple dc circuits that allows them to make intuitive inferences about the electric current based on voltage and resistance. With an effect size of d = 0.94 the new curriculum has proven to be more effective than traditional approaches for teaching electric circuits in a quasi-experimental field study with 790 students from Frankfurt am Main, Germany.

The project described here was aimed at developing and evaluating a novel curriculum with corresponding instructional materials for middle school students on an introduction to Newtonian mechanics, based on physics education research findings. A case study showed that teachers who attended a half-day workshop on the curriculum subsequently enacted these materials in their classrooms appropriately and saw improved student performance. Thus, the project suggests that with only a relatively short amount of training time teachers are able to utilize such materials and consequently to improve teaching and learning in physics classes. We therefore regard it as a promising approach for professional development programs.

Twisted double- and mono-bilayer graphene are graphene-based moiré materials hosting strongly correlated fermions in a gate-tunable conduction band with a topologically non-trivial character. Using unbiased exact diagonalization complemented by unrestricted Hartree-Fock calculations, we find that the strong electron-electron interactions lead to a non-coplanar magnetic state, which has the same symmetries as the tetrahedral antiferromagnet on the triangular lattice and can be thought of as a skyrmion lattice commensurate with the moiré scale, competing with a set of ferromagnetic, topological charge density waves featuring an approximate emergent O(3) symmetry, "rotating" the different charge density wave states into each other. Direct comparison with exact diagonalization reveals that the ordered phases are accurately described within the unrestricted Hartree-Fock approximation. Exhibiting a finite charge gap and Chern number $|C|=1$, the formation of charge density wave order which is intimately connected to a skyrmion lattice phase is consistent with recent experiments on these systems.

The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α–MTDH–VCP complex(es) might enable the treatment of MCL. [ABSTRACT FROM AUTHOR]

Students hold different beliefs about the nature of intelligence. While some believe in intelligence as a fixed trait (fixed mindset), others believe in a more malleable nature of intelligence that can be actively developed (growth mindset). These often unconsciously held beliefs can influence students’ engagement in learning and (therefore) their academic performance. Especially when facing difficulties and/or overcoming setbacks, a growth mindset helps students’ engagement. Students with a growth mindset focus on the learning process, while students holding fixed beliefs feel like they will never be able to master the difficult tasks and tend to give up more often. While most of the mindset research targets students’ general academic mindset, we focus on their physics specific beliefs. Physics is described as ‘challenging’ and ‘difficult’ and in Germany, most students choose to drop physics as soon as possible. We designed and evaluated a physics specific mindset questionnaire, asking students not only about their beliefs about intelligence, but also about their beliefs about learning physics and their (potential) giftedness in physics. The results of this survey show that students’ physics specific mindsets change over time, without targeted interventions. When physics classes begin, in middle school, a majority of students hold a growth mindset in physics, this percentage decreases drastically during the years of learning physics. Aiming to support a growth mindset in physics, we designed a subject-specific intervention based on the domain-general growth mindset interventions, that we tested in a pilot study with 24 students. [ABSTRACT FROM AUTHOR]

Prevention of fatal side effects during cancer therapy of cancer patients with high‐dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug‐mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re‐analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib‐resistant, KIT V560G, D816V‐expressing human mast cell (MC) leukemia (MCL) cell line HMC‐1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF‐CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC‐1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient‐derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT‐driven Imatinib resistance and possible TKI‐induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co‐treatment, potentially reducing the negative side effects associated with MCL therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

Practically all particle separation processes depend on more than one particulate property. In the case of the industrially important froth flotation separation, these properties concern wettability, composition, size and shape. Therefore, it is useful to analyze different particle descriptors when studying the influence of particle wettability and morphology on the separation behavior of particle systems. A common tool for classifying particle separation processes are Tromp functions. Recently, multivariate Tromp functions, computed by means of non-parametric kernel density estimation, have emerged which characterize the separation behavior with respect to multidimensional vectors of particle descriptors. In the present paper, an alternative parametric approach based on copulas is proposed in order to compute multivariate Tromp functions and, in this way, to characterize the separation behavior of particle systems. In particular, bivariate Tromp functions for the area-equivalent diameter and aspect ratio of glass particles with different morphologies and surface modification have been computed, based on image characterization by means of mineral liberation analysis (MLA). Comparing the obtained Tromp functions with one another reveals the combined influence of multiple factors, in this case particle wettability, morphology and size, on the separation behavior and introduces an innovative approach for evaluating multidimensional separation. In addition, we extend the parametric copula-based method for the computation of multivariate Tromp functions, in order to characterize separation processes, also in the case when image measurements are not available for all separated fractions. [ABSTRACT FROM AUTHOR]

The treatment guidelines for basal cell carcinoma (BCC) postulate complete surgical excision using microscopically controlled resection (MOHS) as the gold standard. The need to obtain a small safety margin in the complex anatomical area of the head and neck is very challenging due to the individual characteristics (localization, histology, and size) of tumors and the fact that the postoperative loss of quality of life depends on the surgical defect size. The R1 status is histopathologically defined when the safety margin is less than 1 mm even if there are no tumor cells actually infiltrating the resection margin. Therefore, some studies have already favored a watch-and-wait-strategy in R1 situations. We aimed to evaluate the outcome and recurrence rate of resected BCCs of the head and neck, especially in a histologically proven R1 situation. The outcomes of all resected BCCs observed during a 5-year period (January 2009–December 2013) in a tertiary care center were analyzed. Our standard operating procedure was microscopically controlled surgical excision with reresections until an R0 situation was achieved. In selected patients, an R1 status has been accepted after at least two resections. From the included 191 BCCs, the R1 status was accepted as the final result in 46 (24.1%) cases which had surgically clear margins and were closely followed-up. From 54 patients in the R0 and 40 patients in the R1 group who completed the follow-up (2.4 ± 0.4 years), we observed 0 and 2 local recurrences, respectively (p = 0.19). In cases where frequent follow-up can be secured and the surgical area is delicate, a surgical closure at R1 status can be justified as the recurrence rate is not significantly higher compared with R0. [ABSTRACT FROM AUTHOR]

This study investigated the influence of viscose fibre (VF) geometry on the microstructures and resulting properties of high-density polyethylene (HDPE) composites. Seven types of viscose fibres varying in cross-section shape, linear density, and length were pelletised, compounded into HDPE with a twin-screw extruder, and injection moulded. The microstructures of the composites were characterised by investigating their cross-sections and by extracting the fibres and measuring their lengths using optical microscopy (OM). The mechanical and thermal properties of the composites were characterised using differential scanning calorimetry (DSC), tensile tests, Charpy impact tests, and dynamic mechanical analysis (DMA). The composites prepared using cylindrical fibres with a linear density of 1.7 dtex exhibited the best fibre dispersion, highest orientation, and lowest fibre–fibre contact area. The decrease in the linear density of the cylindrical fibres resulted in increasingly worse dispersion and orientation, while composites containing non-cylindrical fibres exhibited a comparably larger fibre–fibre contact area. The initial fibre length of about 3 to 10 mm decreased to the mean values of 0.29 mm to 0.41 mm during processing, depending on the initial geometry. In general, cylindrical fibres exhibited a superior reinforcing effect in comparison to non-cylindrical fibres. The composites containing cylindrical fibres with a linear density of 1.7 dtex and a length of 5 mm exhibited the best reinforcing effect with an increase in tensile modulus and strength of 323% and 141%, respectively. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (rhEPO) has been shown to exert anti-apoptotic and anti-inflammatory effects after cerebral ischemia. Inflammatory cytokines interleukin-1β and -18 (IL-1β and IL-18) are crucial mediators of apoptosis and are maturated by multiprotein complexes termed inflammasomes. Microglia are the first responders to post-ischemic brain damage and are a main source of inflammasomes. However, the impact of rhEPO on microglial activation and the subsequent induction of inflammasomes after ischemia remains elusive. To address this, we subjected human microglial clone 3 (HMC-3) cells to various durations of oxygen-glucose-deprivation/reperfusion (OGD/R) to assess the impact of rhEPO on cell viability, metabolic activity, oxidative stress, phagocytosis, migration, as well as on the regulation and activation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Administration of rhEPO mitigated OGD/R-induced oxidative stress and cell death. Additionally, it enhanced metabolic activity, migration and phagocytosis of HMC-3. Moreover, rhEPO attenuated post-ischemic activation and regulation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes as well as their downstream effectors CASPASE1 and IL-1β. Pharmacological inhibition of NLRP3 via MCC950 had no effect on the activation of CASPASE1 and maturation of IL-1β after OGD/R, but increased protein levels of NLRP1, NLRC4, and AIM2, suggesting compensatory activities among inflammasomes. We provide evidence that EPO-conveyed anti-inflammatory actions might be mediated via the regulation of the inflammasomes. [ABSTRACT FROM AUTHOR]

Electricity has shaped modern civilization in a way few other discoveries have. Nonetheless, few students successfully develop a basic understanding of voltage, current, and resistance or their mutual relationship in simple DC circuits. Despite teachers' best efforts in the classroom, so-called "alternative conceptions" often prevail after traditional instruction. In particular, voltage has proven to be a difficult concept to teach—many students erroneously think of voltage as a property of electric current. Furthermore, a battery is often considered to be a source of constant current rather than constant voltage. In order to help students develop a better understanding of simple DC circuits, we developed a new curriculum with an accompanying computer simulation that illustrates potential differences in circuits in order to make voltage rather than current the students' primary concept when analyzing circuits. To this end, the curriculum takes typical alternative conceptions into account and builds on students' everyday experiences with air pressure in order to provide them with an immediately tangible counterpart in electric potential. In analogy to air pressure differences that cause an air flow, voltage is introduced as an "electric pressure difference" that causes an electric current. Using the accompanying computer simulation, potential differences are visualized in simple DC circuits using color coding and a height representation. The new curriculum including teaching resources as well as the newly developed computer simulation are both freely available online to teachers and students alike. [ABSTRACT FROM AUTHOR]

I. INTRODUCTION Google has an ambitious mission statement: "... to organize the world's information and make it universally accessible and useful." (1) As part of this mission, Google created what [...]