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Seasonal snow cover has important climatic and ecological implications for the ice-free regions of coastal Greenland. Here we present, for the first time, a dataset of quality-controlled snow depth measurements from nine locations in coastal Greenland with varying periods between 1997 and 2021. Using a simple modelling approach (Δsnow), we estimate snow water equivalent values solely based on the daily time series of snow depth. Snow pit measurements from two locations enable us to evaluate the Δsnow model. As there are very little in situ data available for Greenland, we then test the performance of the regional atmospheric climate model (RACMO2.3p2, 5.5 km spatial resolution) and reanalysis product (CARRA, 2.5 km spatial resolution) at the nine locations with snow observations. Using the combined information from all three data sources, we study spatio-temporal characteristics of the seasonal snow cover in coastal Greenland using the example of six ecologically relevant snow indicators (maximum snow water equivalent, melt onset, melt duration, snow cover duration, snow cover onset, and snow cover end date). In particular, we evaluate the ability of RACMO2.3p2 and CARRA to simulate these snow indicators at the nine different locations, perform a time series analysis of the indicators, and assess their spatial variability. The different locations have considerable spatial and temporal variability in snow cover characteristics, and seasonal maximum snow water equivalent (amount of liquid water stored in the snowpack) values range from less than 50 kg m−2 to greater than 600 kg m−2. The correlation coefficients between maximum snow water equivalent output from Δsnow and CARRA and RACMO are 0.73 and 0.48, respectively. Correlation coefficients are highest for maximum snow water equivalent and snow cover duration, and model and reanalysis output underestimate snow cover onset. We find little evidence of statistically significant (p<0.05) trends at varied periods between 1997 and 2021 except for the earlier onset of snowmelt in Zackenberg (−8 d per decade, p=0.02, based upon RACMO output). While we stress the need for context-specific validation, this study suggests that in most cases snow depth or snow water equivalent output from CARRA can describe spatial and temporal characteristics of seasonal snow cover, particularly changes in melt onset and snow cover end date.

Translational medicine (TM) is an interdisciplinary branch of biomedicine that bridges the gap from bench-to-bedside to improve global health. Fundamental TM skills include interdisciplinary collaboration, communication, critical thinking, and creative problem-solving (4Cs). TM is currently limited in undergraduate biomedical education programs, with little patient contact and opportunities for collaboration between different disciplines. In this study, we developed and evaluated a novel interdisciplinary challenge-based educational concept, grounded in the theoretical framework of experimental research-based education, to implement TM in undergraduate biomedicine and medicine programs. Students were introduced to an authentic clinical problem through an interdisciplinary session with patients, medical doctors, and scientists. Next, students collaborated in groups to design unique laboratory-based research proposals addressing this problem. Stakeholders subsequently rewarded the best proposal with funding to be executed in a consecutive interdisciplinary laboratory course, in which mixed teams of biomedicine and medicine students performed the research in a fully equipped wet laboratory. Written questionnaires and focus groups revealed that students developed 4C skills and acquired a 4C mindset. Working on an authentic patient case and the interdisciplinary setting positively contributed to communication, collaboration, critical thinking, and creative problem-solving skills. Furthermore, students were intrinsically motivated by (i) the relevance of their work that made them feel taken seriously and competent, (ii) the patient involvement that highlighted the societal relevance of their work, and (iii) the acquisition of a realistic view of what doing science in a biomedical research laboratory is. In conclusion, we showcase a widely applicable interdisciplinary challenge-based undergraduate concept fostering TM.

Pupils benefit from adaptive instruction and feedback from their teachers. A prerequisite for providing adaptive instruction is that teachers' diagnostic ability enables them to correctly perceive their pupils' skill level. A short course has been developed to improve primary school teachers' diagnostic ability for engineering. Based on Nickerson's anchoring and adjustment model, the participants became aware of the differences their own and pupils' use of information when constructing technical systems. The Fischer scale was used as a model to understand and identify pupils' development in using such information. The participants were given examples of pupils' reconstructions of technical systems. They were asked to evaluate these work products in four ways: relative and absolute, combined with intuitive and explicit. The results reveal that relative and absolute diagnoses can differ considerably for the same teacher and between teachers, depending on whether they are implicit or explicit. Post-test results show that the course improved the ability to explain the differences between pupils' use of information to construct a technical system. The course also had a strong, significant, positive impact on teachers' self-efficacy beliefs about technology education.

Summary: Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Accurate teacher judgements can enhance pupils' learning about science and technology. This study explored primary school teachers' judgements about their pupils' ability to reconstruct an electrical and a mechanical system. The judgement accuracy of most teachers was poor, gender-biased, and underestimation was more common than overestimation. The teachers' gender or self-efficacy beliefs do not seem to affect their judgement accuracy, whereas greater technical knowledge and teaching experience might be beneficial. The teachers' judgements were primarily based on their estimation of pupils' cognitive abilities and learning behaviour, which both had less bearing on pupils' performance than the teachers had expected. Diagnostic tasks for technical abilities, like the ones used in this study, can be used by primary school teachers working with children aged nine and above to calibrate their judgement accuracy and adapt their teaching to their pupils' varying levels of prior knowledge. Pupils' performance on these non-verbal tasks can reveal unexpected abilities.

This article presents the insights from an evaluation of a transformative policy experiment, in the food domain, conducted at the Swedish Agency of Innovation (Vinnova). To be consistent with the principles and objectives of these policies, it was necessary to implement a formative evaluation approach developed in the Transformative Innovation Policy Consortium (TIPC), that is supportive of experimental policies designed for highly complex and uncertain environments. The article presents the main characteristics of this approach and its differences and similarities with other proposals to assess transformative innovation policies. Next, the article describes how the evaluation was conducted in Vinnova during a 2-year engagement. Subsequently, the main insights gleaned from the process are highlighted in terms of (1) understanding the expectations of actors; (2) what has been learned by doing, from a technical and organizational point of view; and (3) the constraints that emerged during the engagement. It is then argued that the TIPC- formative evaluation approach challenges the role of evaluators, stretching them, and requires different attitudes from those that are common in evaluation practice.

This study aimed to develop and validate, based on the Evidence Centered Design approach, a generic tool to diagnose primary education pupils' prior knowledge of technological systems in primary school classrooms. Two technological devices, namely the Buzz Wire device and the Stairs Marble Track, were selected to investigate whether theoretical underpinnings could be backed by empirical evidence. Study 1 indicated that the tool enabled pupils to demonstrate different aspects of their prior knowledge about a technological system by a wide variety of work products. Study 2 indicated that these work products could be reliably ranked from low to high functionality by technology education experts. Their rank order matched the Fischer-scale-based scoring rules, designed in cooperation with experts in skill development. The solution patterns fit the extended non-parametric Rasch model, confirming that the task can reveal differences in pupils' prior knowledge on a one-dimensional scale. Test--retest reliability was satisfactory. Study 3 indicated that the diagnostic tool was able to capture the range of prior knowledge levels that could be expected of 10 to 12 years old pupils. It also indicated that pupils' scores on standardised reading comprehension and mathematics test had a low predictive value for the outcomes of the diagnostic tool. Overall, the findings substantiate the claim that pupils' prior knowledge of technological systems can be diagnosed properly with the developed tool, which may support teachers in decisions for their technology lessons about content, instruction and support.

Abstract Organoids are engineered 3D miniature tissues that are defined by their organ-like structures, which drive a fundamental understanding of human development. However, current organoid generation methods are associated with low production throughputs and poor control over size and function including due to organoid merging, which limits their clinical and industrial translation. Here, we present a microfluidic platform for the mass production of lumenogenic embryoid bodies and functional cardiospheres. Specifically, we apply triple-jet in-air microfluidics for the ultra-high-throughput generation of hollow, thin-shelled, hydrogel microcapsules that can act as spheroid-forming bioreactors in a cytocompatible, oil-free, surfactant-free, and size-controlled manner. Uniquely, we show that microcapsules generated by in-air microfluidics provide a lumenogenic microenvironment with near 100% efficient cavitation of spheroids. We demonstrate that upon chemical stimulation, human pluripotent stem cell-derived spheroids undergo cardiomyogenic differentiation, effectively resulting in the mass production of homogeneous and functional cardiospheres that are responsive to external electrical stimulation. These findings drive clinical and industrial adaption of stem cell technology in tissue engineering and drug testing.

Abstract Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069.

Summary: Surgical treatment of pediatric congenital heart disease with tissue grafts is a lifesaving intervention. Decellularization to reduce immunogenicity of tissue grafts is an increasingly popular alternative to glutaraldehyde fixation. Here, we present a protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber. We describe steps for 3D printing the flow rig, preparing porcine tissue, and using the flow rig to utilize shear forces for decellularization. We then detail procedures for characterizing the acellular scaffold.For complete details on the use and execution of this protocol, please refer to Vafaee et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. Methods In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR’s technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. Discussion CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. Trial registration CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.