Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals

© 2016 The Author(s) Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message

Can Lean Media Enhance Large Group Learning? An Empirical Investigation of Mobile Information and Communication Technology

A mobile information and communication technology, namely the Mobile Interactive Learning System (MILS), was used to enhance large group learning in a university setting. Expectations concerning learning outcomes, based on the social construction perspective of media richness and constructivist pedagogical principles, were supported. Under similar study conditions, learners with the MILS system demonstrated better (perceived) understanding than those without. Furthermore, learning satisfaction among MILS users was significantly higher. The results were drawn from an empirical evaluation of a structural equation model, and from analyses of variance between the two users groups (with versus without MILS). The results support our hypotheses concerning the impact on understanding and satisfaction. They also suggest that mobile technology affects the learning process, leading to more individual practice and peer influenced learning

Integrase-deficient lentiviral vectors mediate efficient gene transfer to human vascular smooth muscle cells with minimal genotoxic risk

We have previously shown that injury-induced neointima formation was rescued by adenoviral-Nogo-B gene delivery. Integrase-competent lentiviral vectors (ICLV) are efficient at gene delivery to vascular cells but present a risk of insertional mutagenesis. Conversely, integrase-deficient lentiviral vectors (IDLV) offer additional benefits through reduced mutagenesis risk, but this has not been evaluated in the context of vascular gene transfer. Here, we have investigated the performance and genetic safety of both counterparts in primary human vascular smooth muscle cells (VSMC) and compared gene transfer efficiency and assessed the genotoxic potential of ICLVs and IDLVs based on their integration frequency and insertional profile in the human genome. Expression of enhanced green fluorescent protein (eGFP) mediated by IDLVs (IDLV-eGFP) demonstrated efficient transgene expression in VSMCs. IDLV gene transfer of Nogo-B mediated efficient overexpression of Nogo-B in VSMCs, leading to phenotypic effects on VSMC migration and proliferation, similar to its ICLV version and unlike its eGFP control and uninfected VSMCs. Large-scale integration site analyses in VSMCs indicated that IDLV-mediated gene transfer gave rise to a very low frequency of genomic integration compared to ICLVs, revealing a close-to-random genomic distribution in VSMCs. This study demonstrates for the first time the potential of IDLVs for safe and efficient vascular gene transfer

COVID-19 Academic Integrity Violations and Trends: A Rapid Review

The rapid shift from classroom course delivery to online education modalities during the COVID-19 pandemic has had significant impacts on academia. Student loss of face-to-face interaction, the lost social benefits of the educational milieu, and restricted instructor ability to control both the learning environment and assessment process have been significant. The purpose of this paper is to discover if due to the unplanned shift to online course delivery, educators and researchers experienced impacts to academic integrity during the peak of the online shift. A systemic review utilizing the PRISMA methodology of peer reviewed literature published during the period of March 2020 till September 2021 demonstrated that violation types continued to fall within the existing academic integrity constructs of inappropriate information sharing, cheating on exams and assignments, incidents of plagiarism, and falsifying or fabricating information. The results showed that pre-COVID concerns with academic integrity were amplified with previous concerns moving to the forefront. In addition, the rapid shift opened doors for greater opportunity for violations and increased instructor concern especially within the hard sciences and courses with lab-based components. Reinforcing the importance of providing formal academic integrity student and faculty training can be a beneficial intervention to ensure students understand the ethical implications of student behavior and performance during the assessment process. Given the emerging trend pre-COVID that skyrocketed during the pandemic, ensuring academic integrity should remain a key priority for learning institutions

A woman living with osteoarthritis: A case report

Osteoarthritis is a common condition that is typically associated with older adults. Other causes of osteoarthritis, such as those cases resulting from childhood Perthes disease, can affect younger people and frequently have a major impact on the lives of those affected. This case report describes the experiences of one patient with osteoarthritis, using examples of her poetry to illustrate her social, psychological and emotional transformation

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil

Background Breastfeeding has clear short-term benefi ts, but its long-term consequences on human capital are yet to be established. We aimed to assess whether breastfeeding duration was associated with intelligence quotient (IQ), years of schooling, and income at the age of 30 years, in a setting where no strong social patterning of breastfeeding exists. Methods A prospective, population-based birth cohort study of neonates was launched in 1982 in Pelotas, Brazil. Information about breastfeeding was recorded in early childhood. At 30 years of age, we studied the IQ (Wechsler Adult Intelligence Scale, 3rd version), educational attainment, and income of the participants. For the analyses, we used multiple linear regression with adjustment for ten confounding variables and the G-formula. Findings From June 4, 2012, to Feb 28, 2013, of the 5914 neonates enrolled, information about IQ and breastfeeding duration was available for 3493 participants. In the crude and adjusted analyses, the durations of total breastfeeding and predominant breastfeeding (breastfeeding as the main form of nutrition with some other foods) were positively associated with IQ, educational attainment, and income. We identifi ed dose-response associations with breastfeeding duration for IQ and educational attainment. In the confounder-adjusted analysis, participants who were breastfed for 12 months or more had higher IQ scores (diff erence of 3·76 points, 95% CI 2·20–5·33), more years of education (0·91 years, 0·42–1·40), and higher monthly incomes (341·0 Brazilian reals, 93·8–588·3) than did those who were breastfed for less than 1 month. The results of our mediation analysis suggested that IQ was responsible for 72% of the eff ect on income. Interpretation Breastfeeding is associated with improved performance in intelligence tests 30 years later, and might have an important eff ect in real life, by increasing educational attainment and income in adulthood

Observed impacts of COVID-19 on urban CO₂ emissions

Governments restricted mobility and effectively shuttered much of the global economy in response to the COVID‐19 pandemic. Six San Francisco Bay Area counties were the first region in the United States to issue a “shelter‐in‐place” order asking non‐essential workers to stay home. Here we use CO₂ observations from 35 Berkeley Environment, Air‐quality and CO₂ Network (BEACO₂N) nodes and an atmospheric transport model to quantify changes in urban CO₂ emissions due to the order. We infer hourly emissions at 900‐m spatial resolution for 6 weeks before and 6 weeks during the order. We observe a 30% decrease in anthropogenic CO₂ emissions during the order and show that this decrease is primarily due to changes in traffic (–48%) with pronounced changes to daily and weekly cycles; non‐traffic emissions show small changes (–8%). These findings provide a glimpse into a future with reduced CO₂ emissions through electrification of vehicles

Observed impacts of COVID-19 on urban CO₂ emissions

Governments restricted mobility and effectively shuttered much of the global economy in response to the COVID‐19 pandemic. Six San Francisco Bay Area counties were the first region in the United States to issue a “shelter‐in‐place” order asking non‐essential workers to stay home. Here we use CO₂ observations from 35 Berkeley Environment, Air‐quality and CO₂ Network (BEACO₂N) nodes and an atmospheric transport model to quantify changes in urban CO₂ emissions due to the order. We infer hourly emissions at 900‐m spatial resolution for 6 weeks before and 6 weeks during the order. We observe a 30% decrease in anthropogenic CO₂ emissions during the order and show that this decrease is primarily due to changes in traffic (–48%) with pronounced changes to daily and weekly cycles; non‐traffic emissions show small changes (–8%). These findings provide a glimpse into a future with reduced CO₂ emissions through electrification of vehicles