Reactive oxygen species and mitochondrial metabolism in acute myocardial ischaemia reperfusion injury: measurement and modulation

Reactive oxygen species (ROS) are known to play a central role in the pathology of acute myocardial infarction (AMI), where their production is driven by the metabolism of the citric acid cyclic intermediate succinate that accumulates during ischaemia. This is a major driver of damage upon reperfusion of ischaemic tissue. ROS are however increasingly understood to not only have negative effects, but also to act as biological signalling molecules that are able to activate protective pathways. In order to investigate how such antagonistic processes might interplay in the setting of ischaemia/reperfusion injury (IRI), it is necessary to have a tool that allows the titration of a precise amount of ROS, ideally occurring in a manner that closely mimics endogenous ROS production in both location and the exact reactive species. To this end we validate that the mitochondria-targeted compound MitoPQ produces ROS in this manner and also develop a bespoke control compound that matches the molecular properties of MitoPQ closely with the exception that it does not redox cycle at complex I in the mitochondrial respiratory chain. These compounds are then used in model systems in vitro and in the mouse in vivo to show that whilst high doses of exogenous ROS are damaging to the heart undergoing ischaemia/reperfusion, low doses protect the heart against this insult as shown by smaller infarct sizes. Such a biphasic relationship is also seen between mitochondrial ROS and a range of cellular functions, and further allow us to demonstrate clearly for the first time that a primary increase in mitochondrial ROS may result in these changes rather than the other way around. We also validate two further tools for use in vivo that enable the investigation of the effects of changes in mitochondrial redox status. MitoNeoD is an improved probe for the detection of mitochondrial superoxide using the exomarker approach, while MitoCDNB allows the selective disruption of mitochondrial thiol redox state. The metabolic changes occurring in IRI are also investigated, applying mass spectrometry and magnetic resonance spectroscopy to measure the accumulation of succinate during ischaemia and show that the existing cardioprotective strategies of ischaemic preconditioning and moderate cooling do not alter the extent to which succinate is accumulated during ischaemia. The use of disodium malonate to inhibit the metabolism of succinate at reperfusion is conversely found to protect the heart against IRI. A pilot experiment is also conducted to validate a protocol of volitional exercise post AMI that has been reported to have beneficial effects on heart function during the development of heart failure with a view to investigating a potential role of succinate, but no difference is observed between exercised and sedentary mice in our hands.Medical Research Council, Raymond and Beverly Sackler Foundatio

Federal Programs Available to Unemployed Workers

[Excerpt] Four groups of federal programs target unemployed workers: unemployment insurance, health care assistance, job search assistance, and training. This report presents information on federal programs targeted to unemployed workers specifically, but does not attempt to discuss means-tested programs (such as Medicaid or SSI) that are available regardless of employment status. This report will be updated with major new legislation

Diisopropylamide and TMP turbo-grignard reagents : a structural rationale for their contrasting reactivities

A neutral dimeric molecule in crystal form, the diisopropylamido turbo-Grignard reagent "(iPr2N)MgCl⋅LiCl" (see structure; blue N, red O, green Mg, yellow Cl, black C) separates into several charged ate species in dynamic exchange with each other in THF solution as determined by a combination of EXSY and DOSY NMR studies

ST-MLP: A Cascaded Spatio-Temporal Linear Framework with Channel-Independence Strategy for Traffic Forecasting

The criticality of prompt and precise traffic forecasting in optimizing traffic flow management in Intelligent Transportation Systems (ITS) has drawn substantial scholarly focus. Spatio-Temporal Graph Neural Networks (STGNNs) have been lauded for their adaptability to road graph structures. Yet, current research on STGNNs architectures often prioritizes complex designs, leading to elevated computational burdens with only minor enhancements in accuracy. To address this issue, we propose ST-MLP, a concise spatio-temporal model solely based on cascaded Multi-Layer Perceptron (MLP) modules and linear layers. Specifically, we incorporate temporal information, spatial information and predefined graph structure with a successful implementation of the channel-independence strategy - an effective technique in time series forecasting. Empirical results demonstrate that ST-MLP outperforms state-of-the-art STGNNs and other models in terms of accuracy and computational efficiency. Our finding encourages further exploration of more concise and effective neural network architectures in the field of traffic forecasting

Accessible heavier s-block dihydropyridines : structural elucidation and reactivity of isolable molecular hydride sources

The straightforward metathesis of 1-lithio-2-tbutyl-1,2-dihydropyridine using metal tert-butoxide (Na/K) has resulted in the first preparation and isolation of a series of heavier alkali metal dihydropyridines. By employing donors, TMEDA, PMDETA and THF, five new metallodihydropyridine compounds were isolated and fully characterised. Three distinct structural motifs have been observed; a dimer, a dimer of dimers and a novel polymeric dihydropyridylpotassium compound, and the influence of cation π-interactions therein has been discussed. Thermal volatility analysis has shown that these complexes have the potential to be used as simple isolable sodium or potassium hydride surrogates, which is confirmed in test reactions with benzophenone

'It's a film' : medium specificity as textual gesture in Red road and The unloved

British cinema has long been intertwined with television. The buzzwords of the transition to digital media, 'convergence' and 'multi-platform delivery', have particular histories in the British context which can be grasped only through an understanding of the cultural, historical and institutional peculiarities of the British film and television industries. Central to this understanding must be two comparisons: first, the relative stability of television in the duopoly period (at its core, the licence-funded BBC) in contrast to the repeated boom and bust of the many different financial/industrial combinations which have comprised the film industry; and second, the cultural and historical connotations of 'film' and 'television'. All readers of this journal will be familiar – possibly over-familiar – with the notion that 'British cinema is alive and well and living on television'. At the end of the first decade of the twenty-first century, when 'the end of medium specificity' is much trumpeted, it might be useful to return to the historical imbrication of British film and television, to explore both the possibility that medium specificity may be more nationally specific than much contemporary theorisation suggests, and to consider some of the relationships between film and television manifest at a textual level in two recent films, Red Road (2006) and The Unloved (2009)

Adding a structural context to the deprotometalation and trans-metal trapping chemistry of phenyl-substituted benzotriazole

Organometallic bases are becoming increasingly complex, because mixing components can lead to bases superior to single-component bases. To better understand this superiority, it is useful to study metalated intermediate structures prior to quenching. This study is on 1-phenyl-1H-benzotriazole, which was previously deprotonated by an in situ ZnCl2• TMEDA/LiTMP (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidide) mixture and then iodinated. Herein, reaction with LiTMP exposes the deficiency of the single-component base as the crystalline product obtained was [{4-R-1-(2-lithiophenyl)-1H-benzotriazole• 3THF}2], [R=2-C6H4(Ph)NLi], in which ring opening of benzotriazole and N2 extrusion had occurred. Supporting lithiation by adding iBu2Al(TMP) induces trans-metal trapping, in which C-Li bonds transform into C-Al bonds to stabilise the metalated intermediate. X-ray diffraction studies revealed homodimeric [(4-R′-1-phenyl-1H-benzotriazole)2], [R′=(iBu)2Al(μ-TMP)Li], and its heterodimeric isomer [(4-R′-1-phenyl-1H-benzotriazole){2-R′-1-phenyl-1H-benzotriazole}], whose structure and slow conformational dynamics were probed by solution NMR spectroscopy