Improving the electronic communication between a porphyrin core and peripheral substituents: towards enhanced solar energy conversion

The conversion of solar energy into a usable form via photocatalysis and photovoltaics is a continually growing area of research due to the ever-growing need to shift away from fossil fuel-derived energy. Porphyrins have become a focal point for the design of new dyes and photocatalysts due to their optical properties, high stability, scope of functionalisation and cheapness. This work synthesised a series of meso-substituted porphyrins with furan and thiophene based groups in an attempt to extend the conjugation of the porphyrin system. The synthesis of trans-5,15-di(methyl furan-2-carboxylate)10,20-diphenylporphyrin (26a) and trans-5,15-di(methylthiophene-2-carboxylate)10,20-diphenylporphyrin (27a) followed a Suzuki-Miyaura cross-coupling methodology. To get to this point, a modified Lindsey 2+2 condensation reaction, followed by di-bromination of a trans-5,15-diphenyl porphyrin was completed. The modified condensation reaction was the foundation of the synthetic pathway and resulted in exceptional yields of >40 %. Initially a palladium catalysed Miyaura-borylation of the furan and thiophene rings were undertaken but following complications in purification, an alternative C-H activated borylation reaction was undertaken using an [Ir(COD)(OMe)]2 catalyst. This resulted in the successful synthesis of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-furancarboxylate (35) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophene-carboxylate (36), with yields of 51 % and 56 % respectively. Finally, the furan and thiophene-substituted porphyrins were synthesised in reasonable yields. These porphyrins were characterised and studied by UV-Vis spectroscopy and emission studdies. Both techniques gave evidence of increased extended conjugation in the free-base porphyrins compared to porphyrins with phenyl substituents. Supporting density functional theory (DFT) calculations confirmed that the red shift in the spectral data of the porphyrins containing the different 5-membered rings were due to a decrease in the dihedral angles along the porphyrin plane. Future work aims to tether the porphyrins to a dimolybdenum paddlewheel complex, so that the extent of the conjugation can be fully studied

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

Identifying models of HIV care and treatment service delivery in Tanzania, Uganda, and Zambia using cluster analysis and Delphi survey.

BACKGROUND: Organization of HIV care and treatment services, including clinic staffing and services, may shape clinical and financial outcomes, yet there has been little attempt to describe different models of HIV care in sub-Saharan Africa (SSA). Information about the relative benefits and drawbacks of different models could inform the scale-up of antiretroviral therapy (ART) and associated services in resource-limited settings (RLS), especially in light of expanded client populations with country adoption of WHO's test and treat recommendation. METHODS: We characterized task-shifting/task-sharing practices in 19 diverse ART clinics in Tanzania, Uganda, and Zambia and used cluster analysis to identify unique models of service provision. We ran descriptive statistics to explore how the clusters varied by environmental factors and programmatic characteristics. Finally, we employed the Delphi Method to make systematic use of expert opinions to ensure that the cluster variables were meaningful in the context of actual task-shifting of ART services in SSA. RESULTS: The cluster analysis identified three task-shifting/task-sharing models. The main differences across models were the availability of medical doctors, the scope of clinical responsibility assigned to nurses, and the use of lay health care workers. Patterns of healthcare staffing in HIV service delivery were associated with different environmental factors (e.g., health facility levels, urban vs. rural settings) and programme characteristics (e.g., community ART distribution or integrated tuberculosis treatment on-site). CONCLUSIONS: Understanding the relative advantages and disadvantages of different models of care can help national programmes adapt to increased client load, select optimal adherence strategies within decentralized models of care, and identify differentiated models of care for clients to meet the growing needs of long-term ART patients who require more complicated treatment management

A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

Funding Statement For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. MND-SMART is funded by grants from MND Scotland, My Name'5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. The Chandran lab is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. E.E is a clinical academic fellow jointly funded by MND Scotland (MNDS) and the Chief Scientist Office (CSO) (217ARF R45951). A.R.M. was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). A.Salzinger is funded by Marie Sklodowska-Curie actions Innovative Training Network (ITN). B.T.S is funded by Rowling fellowship.Preprin

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease : Using systematic reviews to inform expert consensus

Funding Information: For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. MND-SMART is funded by grants from MND Scotland, My Name’5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. The Chandran lab is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. EE is a clinical academic fellow jointly funded by MND Scotland (MNDS) and the Chief Scientist Office (CSO) (217ARF R45951). ARM was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). ASalzinger is funded by Marie Sklodowska-Curie actions Innovative Training Network (ITN). BTS is funded by Rowling fellowship.Peer reviewedPublisher PD