A Barrel‐Shaped Metal‐Organic Blue‐Box Analog with Photo‐/Redox‐Switchable Behavior

International audienceDonor acceptor interactions are ubiquitous in the design and understanding of host-guest complexes. Despite their non-covalent nature, they can readily dictate the self-assembly of complex architectures. Here, we present a photo-/redox-switchable metal-organic nanocapsule, assembled using lanthanide ions and viologen building blocks, that relies on such donor-acceptor interactions. We highlight the potential of this unique barrel-shaped structure for the encapsulation of suitable electron donors, akin to the well-investigated "blue-box" macrocycles. The light-triggered reduction of the viologen units has been investigated by single-crystal-to-single-crystal X-ray diffraction experiments, complemented by magnetic, optical and solid-state electrochemical characterizations. Density functional theory (DFT) calculations were employed to suggest the most likely electron donor in the light-triggered reduction of the viologen-based ligand

(Digital competencies, curriculum and physical education teacher Education)

The text aims to identify themes related to digital competences in Physical Education teacher training proposals in three countries. By content analysis, statements about media and technology in curricular documents from three higher education courses in Physical Education in Australia, Brazil and New Zealand are categorized according to theoretical frameworks of digital skills for UNESCO and European Union teachers. The categories of “Uses of technology in the didactic field” and “Promotion of pedagogical aspects” are the most explored. New Zealand and Australia’s proposals cover all the dimensions discussed, in contrast to the Brazilian one. It defends an organic articulation of the methodological, critical and productive dimensions of media-education in teacher educatio

The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein

In mammalian cells, MCTs (monocarboxylate transporters) require association with an ancillary protein to enable plasma membrane expression of the active transporter. Basigin is the preferred binding partner for MCT1, MCT3 and MCT4, and embigin for MCT2. In rat and rabbit erythrocytes, MCT1 is associated with embigin and basigin respectively, but its sensitivity to inhibition by AR-C155858 was found to be identical. Using RT (reverse transcription)–PCR, we have shown that Xenopus laevis oocytes contain endogenous basigin, but not embigin. Co-expression of exogenous embigin was without effect on either the expression of MCT1 or its inhibition by AR-C155858. In contrast, expression of active MCT2 at the plasma membrane of oocytes was significantly enhanced by co-expression of exogenous embigin. This additional transport activity was insensitive to inhibition by AR-C155858 unlike that by MCT2 expressed with endogenous basigin that was potently inhibited by AR-C155858. Chimaeras and C-terminal truncations of MCT1 and MCT2 were also expressed in oocytes in the presence and absence of exogenous embigin. L-Lactate Km values for these constructs were determined and revealed that the TM (transmembrane) domains of an MCT, most probably TM7–TM12, but not the C-terminus, are the major determinants of L-lactate affinity, whereas the associated ancillary protein has little or no effect. Inhibitor titrations of lactate transport by these constructs indicated that embigin modulates MCT2 sensitivity to AR-C155858 through interactions with both the intracellular C-terminus and TMs 3 and 6 of MCT2. The C-terminus of MCT2 was found to be essential for its expression with endogenous basigin

Tunable Energy-Transfer Process in Heterometallic MOF Materials Based on 2,6-Naphthalenedicarboxylate: Solid-State Lighting and Near-Infrared Luminescence Thermometry

Trivalent lanthanide ions (Ln3+) are used to prepare a plethora of coordination compounds, with metal-organic frameworks (MOFs) being among the most sought-after in recent years. The porosity of Ln-MOFs is often complemented by the luminescence imparted by the metal centers, making them attractive multifunctional materials. Here, we report a class of three-dimensional (3D) MOFs obtained from a solvothermal reaction between 2,6-naphthalenedicarboxylic acid (H2NDC) and lanthanide chlorides, yielding three types of compounds depending on the chosen lanthanide: [LnCl(NDC)(DMF)] for Ln3+ = La3+, Ce3+, Pr3+, Nd3+, Sm3+ (type 1), [Eu(NDC)1.5(DMF)]·0.5DMF (type 2), and [Ln2(NDC)3(DMF)2] for Ln3+ = Tb3+, Dy3+, Y3+, Er3+, Yb3+ (type 3). Photoluminescent properties of selected phases were explored at room temperature. The luminescence thermometry capability of Yb3+-doped Nd-MOF was fully investigated in the 15-300 K temperature range under 365 and 808 nm excitation. To describe the optical behavior of the isolated MOFs, we introduce the total energy-transfer balance model. Therein, the sum of energy-transfer rates is considered along with its dependence on the temperature - the sign, magnitude, and variation of this parameter - permitting to afford a thorough interpretation of the observed behavior of the luminescent species of all materials presented here. The combination of novel theoretical and experimental studies presented herein to describe energy-transfer processes in luminescent materials can pave the way toward the design of MOF-based chemical and physical sensors working in an optical range of interest for biomedical applications.Fil: Gomez, Germán Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Marin, Riccardo. University of Ottawa; CanadáFil: Carneiro Neto, Albano N.. Universidade de Aveiro; PortugalFil: Botas, Alexandre M. P.. Universidade de Aveiro; PortugalFil: Ovens, Jeffrey. University of Ottawa; CanadáFil: Kitos, Alexandros A.. University of Ottawa; CanadáFil: Bernini, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Carlos, Luís D.. Universidade de Aveiro; PortugalFil: Soler Illia, Galo Juan de Avila Arturo. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Murugesu, Muralee. University of Ottawa; Canad

Challenging the 'New Professionalism': from managerialism to pedagogy?

In recent years there have been changes made to the conceptualisation of continuing professional development for teachers in both the Scottish and English systems of education. These changes have been instigated by successive UK governments (and more recently, by the Scottish Executive), together with the General teaching Council for Scotland (GTCS) and the General Teaching Council for England (GTCE). This paper argues that these changes have not provided a clear rationale for CPD, but instead have introduced tensions between the concept of teacher education and that of training. The need for a less confused understanding of CPD and its purposes is underlined, as is the need for school based approaches to continuing teacher education. Arguably, teacher education must move from technicist emphases to a model which integrates the social processes of change within society and schools with the individual development and empowerment of teachers

Faculty members engaging in transformative PETE: a feminist perspective

The purpose of this study was to describe sport pedagogy faculty members’ (FMs) efforts at engaging in transformative physical education teacher education (T-PETE). T-PETE stresses the importance of FMs creating social change through their pedagogical approach and begins by asking preservice teachers (PTs) to reflect on their perspectives and practices (Tinning, 2017 Tinning, R. (2017). Transformative pedagogies and physical education. In C. Ennis (Ed.), The Routledge handbook of physical education pedagogies (pp. 295–306). New York: Taylor & Francis. [Google Scholar]. Transformative pedagogies and physical education. In C. Ennis (Ed.), The Routledge handbook of physical education pedagogies (pp. 295–306). New York: Taylor & Francis; Ukpokodu, 2009. The practice of transformative pedagogy. Journal on Excellence in College Teaching, 20(2), 43–67.). Participants were three white, female, able-bodied, lesbian/gay sport pedagogy FMs. The study was conducted in the United States. Feminist theory and feminist pedagogy drove data collection and analysis. Data were collected by employing a series of qualitative methods. An inductive and deductive analysis revealed that FMs had specific T-PETE goals, content, and pedagogies. Furthermore, several factors served to facilitate and limit the FMs’ effectiveness when engaging in T-PETE. The findings suggest that program-wide PETE reform is necessary in the United States for creating social change, and influencing PTs perspectives and practices. In addition, they suggest that American PETE programs might benefit from greater diversity among the FMs who staff them

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965

SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMP-activated protein kinase (AMPK) inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965

AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10

In the present study we characterize the properties of the potent MCT1 (monocarboxylate transporter 1) inhibitor AR-C155858. Inhibitor titrations of L-lactate transport by MCT1 in rat erythrocytes were used to determine the Ki value and number of AR-C155858-binding sites (Et) on MCT1 and the turnover number of the transporter (kcat). Derived values were 2.3±1.4 nM, 1.29±0.09 nmol per ml of packed cells and 12.2±1.1 s−1 respectively. When expressed in Xenopus laevis oocytes, MCT1 and MCT2 were potently inhibited by AR-C155858, whereas MCT4 was not. Inhibition of MCT1 was shown to be time-dependent, and the compound was also active when microinjected, suggesting that AR-C155858 probably enters the cell before binding to an intracellular site on MCT1. Measurement of the inhibitor sensitivity of several chimaeric transporters combining different domains of MCT1 and MCT4 revealed that the binding site for AR-C155858 is contained within the C-terminal half of MCT1, and involves TM (transmembrane) domains 7–10. This is consistent with previous data identifying Phe360 (in TM10) and Asp302 plus Arg306 (TM8) as key residues in substrate binding and translocation by MCT1. Measurement of the Km values of the chimaeras for L-lactate and pyruvate demonstrate that both the C- and N-terminal halves of the molecule influence transport kinetics consistent with our proposed molecular model of MCT1 and its translocation mechanism that requires Lys38 in TM1 in addition to Asp302 and Arg306 in TM8 [Wilson, Meredith, Bunnun, Sessions and Halestrap (2009) J. Biol. Chem. 284, 20011–20021]