Mechanistic Insight into Novel Sulfoxide Containing SABRE Polarisation Transfer Catalysts

Signal Amplification By Reversible Exchange (SABRE) is a hyperpolarisation technique that commonly uses [Ir(H)2(carbene)(substrate)3]Cl complexes to catalytically transfer magnetisation from para-hydrogen derived hydride ligands to coordinated substrates. Here, we explore the reactivity of a novel class of such catalysts based on sulfoxide containing [IrCl(H)2(carbene)(DMSO)2], which are involved in the hyperpolarisation of pyruvate using SABRE. We probe the reactivity of this species by NMR and DFT and upon reaction with sodium pyruvate establish the formation of two isomers of [Ir(H)2(η2-pyruvate)(DMSO)(IMes)]. Studies with related disodium oxalate yield [Ir2(H)4(IMes)2(DMSO)2(κ2-η2-Oxalate)] that is characterised by NMR and X-ray diffraction

Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts.

BACKGROUND: Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. RESULTS: We identify sixty-nine significant cis-eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5, ZBTB38, CPE, GNA12, RIPK3, IQGAP1 and FLCN. Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3, show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. CONCLUSION: We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area

Networked Learning in 2021: A Community Definition

Introduction (Networked Learning Editorial Collective): Since the turn of this century, much of the world has undergone a tectonic socio-technological change. Computers have left the isolated basements of research institutes and entered people's homes. Network connectivity has advanced from slow and unreliable modems to high-speed broadband. Devices have evolved: from stationary desktop computers to ever-present, always-connected smartphones. These developments have been accompanied by new digital practices, and changing expectations, not least in education, where enthusiasm for digital technologies has been kindled by quite contrasting sets of values. For example, some critical pedagogues working in the traditions of Freire and Illich have understood computers as novel tools for political and social emancipation, while opportunistic managers in cash-strapped universities have seen new opportunities for saving money and/or growing revenues. Irrespective of their ideological leanings, many of the early attempts at marrying technology and education had some features in common: instrumentalist understanding of human relationships with technologies, with a strong emphasis on practice and 'what works'. It is now clear that, in many countries, managerialist approaches have provided the framing, while local constraints and exigencies have shaped operational details, in fields such as e-learning, Technology Enhanced Learning, and others waving the 'Digital' banner. Too many emancipatory educational movements have ignored technology, burying their heads in the sand, or have wished it away, subscribing toa new form of Luddism, even as they sense themselves moving to the margins. But this situation is not set in stone. Our postdigital reality results from a complex interplay between centres and margins. Furthermore, the concepts of centres and margins 'have morphed into formations that we do not yet understand, and they have created (power) relationships which are still unsettled. The concepts … have not disappeared, but they have become somewhat marginal in their own right.' (Jandrić andHayes 2019) Social justice and emancipation are as important as ever, yet they require new theoretical reconfigurations and practices fit for our socio-technological moment. In the 1990s, networked learning (NL) emerged as a critical response to dominant discourses of the day. NL went against the grain in two main ways. First, it embarked on developing nuanced understandings of relationships between humans and technologies; understandings which reach beyond instrumentalism and various forms of determinism. Second, NL embraced the emancipatory agenda of the critical pedagogy movement and has, in various ways, politically committed to social justice (Beaty et al. 2002; Networked Learning Editorial Collective 2020). Gathered around the biennial Networked Learning Conference,1 the Research in NetworkedLearning book series,2 and a series of related projects and activities, the NL community has left a significant trace in educational transformations over the last few decades. Twenty years ago, founding members of the NL community offered a definition of NL which has strongly influenced the NL community’s theoretical perspectives and research approaches (Goodyear et al. 2004).3 Since then, however, the world has radically changed. With this in mind, the Networked Learning Editorial Collective (NLEC) recently published a paper entitled 'Networked Learning: InvitingRedefinition' (2020). In line with NL's critical agenda, a core goal for the paper was to open up a broad discussion about the current meaning and understandings of NL and directions for its further development. The current collectively authored paper presents the responses to the NLEC's open call. With 40 contributors coming from six continents and working across many fields of education, the paper reflects the breadth and depth of current understandings of NL. The responses have been collated, classified into main themes, and lightly edited for clarity. One of the responders, Sarah Hayes, was asked to write aconclusion. The final draft paper has undergone double open review. The reviewers, Laura Czerniewicz and Jeremy Knox, are acknowledged as authors. Our intention, in taking this approach, has been to further stimulate democratic discussion about NL and to prompt some much-needed community-building.lic

ABR analysis of mice at 6 and 12 months of age.

*<p>denotes a significant p value (p<0.05).</p

Hearing analysis using ABR.

<p>Mice were subjected to ABR analysis at 6 months of age (A) and at 12 months of age (B) to determine their hearing ability. At 6 months, female mice possessed significantly better hearing than males at 8, 16 and 32 KHz. However, at 12 months of age, the hearing of the females had worsened compared to males. Error bars equal the SEM.</p

Analysis of cochlea bone.

<p>Bone mineral density of the cochlea was calculated for female and male mice using microCT scanning (panel A). Female mice possessed a significantly lower BMD index than male mice (p = 0.014). Subsequent analysis revealed that the average size of the osteocyte lacunae was significantly larger in the female mice compared to the males (p<0.001). Error bars denote the SEM and * indicates a significance of p<0.05.</p

Representative histological sections of cochlea bone for female and male mice.

<p>H&E stained sections of cochlea bone revealed that the osteocyte lacunae (arrows) appeared larger in the female mice (panel A) compared to the male mice (pane B). Scale bars equal 50 µm.</p