Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal ...transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
As online and blended learning has become common place educational strategy in higher education, educators need to reconceptualise fundamental issues of teaching, learning and assessment in non ...traditional spaces. These issues include concepts such as validity and reliability of assessment in online environments in relation to serving the intended purposes, as well as understanding how formative assessment functions within online and blended learning. This article provides a systematic qualitative review of the research literature on online formative assessment in higher education. As an integrative narrative review, the method applied in this review entailed systematic searching, reviewing, and writing this review of the literature to bring together key themes and findings of research in this field. The authors applied qualitative thematic criteria in selecting and reviewing the available literature from which they focused on identifying and analyzing the core themes that are central to the concept of formative assessment with a key focus on application of formative assessment within blended and online contexts. Various techniques were identified for formative assessment by the individual, peers and the teacher, many of which were linked with online tools such as self-test quiz tools, discussion forums and e-portfolios. The benefits identified include improvement of learner engagement and centrality in the process as key actors, including the development of a learning community. The key findings are that effective online formative assessment can foster a learner and assessment centered focus through formative feedback and enhanced learner engagement with valuable learning experiences. Ongoing authentic assessment activities and interactive formative feedback were identified as important characteristics that can address threats to validity and reliability within the context of online formative assessment.
► Formative assessment functions within online learning. ► Formative assessment by the individual, peers and the teacher. ► Threats to validity and reliability in the context of online formative assessment. ► Ongoing authentic assessment deters threats to validity and reliability. ► Interactive formative feedback addresses threats to validity and reliability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Post-translational modifications (PTMs) greatly expand the structures and functions of proteins in nature
. Although synthetic protein functionalization strategies allow mimicry of PTMs
, as well as ...formation of unnatural protein variants with diverse potential functions, including drug carrying
, tracking, imaging
and partner crosslinking
, the range of functional groups that can be introduced remains limited. Here we describe the visible-light-driven installation of side chains at dehydroalanine residues in proteins through the formation of carbon-centred radicals that allow C-C bond formation in water. Control of the reaction redox allows site-selective modification with good conversions and reduced protein damage. In situ generation of boronic acid catechol ester derivatives generates RH
C
radicals that form the native (β-CH
-γ-CH
) linkage of natural residues and PTMs, whereas in situ potentiation of pyridylsulfonyl derivatives by Fe(II) generates RF
C
radicals that form equivalent β-CH
-γ-CF
linkages bearing difluoromethylene labels. These reactions are chemically tolerant and incorporate a wide range of functionalities (more than 50 unique residues/side chains) into diverse protein scaffolds and sites. Initiation can be applied chemoselectively in the presence of sensitive groups in the radical precursors, enabling installation of previously incompatible side chains. The resulting protein function and reactivity are used to install radical precursors for homolytic on-protein radical generation; to study enzyme function with natural, unnatural and CF
-labelled post-translationally modified protein substrates via simultaneous sensing of both chemo- and stereoselectivity; and to create generalized 'alkylator proteins' with a spectrum of heterolytic covalent-bond-forming activity (that is, reacting diversely with small molecules at one extreme or selectively with protein targets through good mimicry at the other). Post-translational access to such reactions and chemical groups on proteins could be useful in both revealing and creating protein function.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
With fusion device performance hinging on the edge pedestal pressure, it is imperative to experimentally understand the physical mechanism dictating the pedestal characteristics and to validate and ...improve pedestal predictive models. This Letter reports direct evidence of density and magnetic fluctuations showing the stiff onset of an edge instability leading to the saturation of the pedestal on the Alcator C-Mod tokamak. Edge stability analyses indicate that the pedestal is unstable to both ballooning mode and kinetic ballooning mode in agreement with observations.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Aims/hypothesis
It is well established that diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. Observational studies suggest that a history of diabetic foot ...ulceration (DFU) may increase this risk further still. We sought to determine to what extent DFU is associated with excess risk over and above diabetes.
Methods
We identified studies reporting on associations of DFU with CVD and all-cause mortality. We obtained data on incident events of all-cause mortality, fatal myocardial infarction and fatal stroke. Study-specific estimates were pooled using a random-effects meta-analysis and the statistical heterogeneity of included studies was assessed using the
I
2
statistic.
Results
The eight studies included reported on 3,619 events of all-cause mortality during 81,116 person-years of follow-up. DFU was associated with an increased risk of all-cause mortality (RR 1.89, 95% CI 1.60, 2.23), fatal myocardial infarction (2.22, 95% CI 1.09, 4.53) and fatal stroke (1.41, 95% CI 0.61, 3.24). CVD mortality accounted for a similar proportion of deaths in DFU and non-DFU patients.
Conclusions/interpretation
Patients with DFU have an excess risk of all-cause mortality, compared with patients with diabetes without a history of DFU. This risk is attributable, in part, to a greater burden of CVD. If this result is validated in other studies, strategies should evaluate the role of further aggressive CVD risk modification and ulcer prevention in those with DFU.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tissue-like structures from human pluripotent stem cells containing multiple cell types are transforming our ability to model and understand human development and disease. Here we describe a protocol ...to generate cardiomyocytes (CMs), cardiac fibroblasts (CFs) and cardiac endothelial cells (ECs), the three principal cell types in the heart, from human induced pluripotent stem cells (hiPSCs) and combine them in three-dimensional (3D) cardiac microtissues (MTs). We include details of how to differentiate, isolate, cryopreserve and thaw the component cells and how to construct and analyze the MTs. The protocol supports hiPSC-CM maturation and allows replacement of one or more of the three heart cell types in the MTs with isogenic variants bearing disease mutations. Differentiation of each cell type takes ~30 d, while MT formation and maturation requires another 20 d. No specialist equipment is needed and the method is inexpensive, requiring just 5,000 cells per MT.
Order parameter symmetry is one of the basic characteristics of a superconductor. The heavy fermion compound UPt3 provides a rich system for studying the competition between superconductivity and ...other forms of electronic order and exhibits two distinct superconducting phases that are characterized by different symmetries. We fabricated a series of Josephson tunnel junctions on the as-grown surfaces of UPt3 single crystals spanning the a-b plane. By measuring their critical current, we mapped out the magnitude of the superconducting order parameter as a function of the momentum-space direction and temperature. In the high-temperature phase, we observed a sharp node in the superconducting gap at 45 degrees with respect to the a axis; an out-of-phase component appeared in the low-temperature phase, creating a complex order parameter.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
IMPORTANCE: Reperfusion is a key factor for clinical outcome in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT) for large-vessel intracranial occlusion. ...However, data are scarce on the association between the time from onset and reperfusion results. OBJECTIVE: To analyze the rate of reperfusion after EVT started at different intervals after symptom onset in patients with AIS. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of individual patient data from 7 randomized trials of the Highly Effective Reperfusion Using Multiple Endovascular Devices (HERMES) group. This is a multicenter cohort study of the intervention arm of randomized clinical trials included in the HERMES group. Patients with anterior circulation AIS who underwent EVT for M1/M2 or intracranial carotid artery occlusion were included. Each trial enrolled patients according to its specific inclusion and exclusion criteria. Data on patients eligible but not enrolled (eg, refusals or exclusions) were not available. All analyses were performed by the HERMES biostatistical core laboratory using the pooled database. Data were analyzed between December 2010 and April 2015. MAIN OUTCOMES AND MEASURES: Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score of 2b/3 at the end of the EVT procedure adjusted for age, occlusion location, pretreatment intravenous thrombolysis, and clot burden score and was analyzed in relation to different intervals (onset, emergency department arrival, imaging, and puncture) using mixed-methods logistic regression. RESULTS: Among the 728 included patients, with a mean (SD) age of 65.4 (13.5) years and of whom 345 were female (47.4%), decreases in rates of successful reperfusion defined as a thrombolysis in cerebral infarction score of 2b/3 were observed with increasing time from admission or first imaging to groin puncture. The magnitude of effect was a 22% relative reduction (odds ratio, 0.78; 95% CI, 0.64-0.95) per additional hour between admission and puncture and a 26% relative reduction (odds ratio, 0.74; 95% CI, 0.59-0.93) per additional hour between imaging and puncture. CONCLUSIONS AND RELEVANCE: Because the probability of reperfusion declined significantly with time between hospital arrival and groin puncture, we provide additional arguments for minimizing the intervals after symptom onset in anterior circulation acute ischemic stroke.
Aim
Since the start of the COVID‐19 pandemic, there have been many changes in the presenting complaints in paediatric emergency departments (EDs). We sought to characterise the impact of the COVID‐19 ...pandemic on bicycle‐related injuries in children presenting to a tertiary care paediatric ED.
Methods
We conducted a descriptive, cross‐sectional study of ED visits to a large urban tertiary children's hospital, comparing March to October 2020 (the study period) to the same date range 2 years prior (i.e. March to October 2018–2019). We included children 0–17.99 years presenting for a bicycle‐related injury. We compared absolute visit counts of bike injuries per month, demographics, triage acuity, injury type and disposition.
Results
A total of 1215 bike‐related visits were analysed. There were 234 presentations in 2018 (March to October), 305 in 2019, and 676 in 2020. Overall, the mean age was 9.5 years (standard deviation 5.5–13.5), there were 67% males, median Canadian Emergency Department Triage and Acuity Scale score was 3 (interquartile range 3–4) and the most common injuries were fractures (n = 471, 38.8%). There were significantly more bike injuries presenting to the ED per month in the COVID group, 33.7(17.9) versus 84.5(61.4) (two‐tailed P value = 0.041). There was no statistical difference in ‘severe injuries’ pre‐ versus post‐COVID (odds ratio 0.815 (95% confidence interval 0.611–1.088), P = 0.165).
Conclusion
There was a significant increase in bicycle‐related injuries presenting to our ED during the pandemic, compared to previous years. Evaluating these trends will allow for the exploration of harm reduction strategies for preventing future bicycle‐related injuries.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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