Photochemistry of [Ru(pytz)(btz)2]2+and Characterization of a κ1-btz Ligand-Loss Intermediate

We report the synthesis, characterisation and photochemical reactivity of the triazole-containing complex [Ru(pytz)(btz)2]2+ (1, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, btz = 1,1’-dibenzyl-4,4’-bi-1,2,3-triazolyl). The UV-visible absorption spectrum of 1 exhibits pytz- and btz-centred 1MLCT bands at 365 and 300 nm respectively. Upon photo-excitation, acetonitrile solutions of 1 undergo conversion to the ligand loss intermediate, trans-[Ru(pytz)(2-btz)(1-btz)(NCMe)]2+ (2, 363 = 0.013) and ultimately to the ligand loss product trans-[Ru(pytz)(btz)(NCMe)2]2+ (3), both of which are observed and characterised by 1H NMR spectroscopy. Time-dependent density functional theory calculations reveal that the S1 state of the complex has primarily HOMOLUMO pytz-based 1MLCT character. Data show that the 3MLCT and 3MC states are in close energetic proximity ( 0.11 eV to 2 d.p.) and that the T1 state from a single point triplet state calculation at the S0 geometry suggests 3MC character. Optimisation of the T1 state of the complex starting from the ground state geometry leads to elongation of the two Ru-N(btz) bonds cis to the pytz ligand to 2.539 and 2.544 Å leading to a psuedo 4-coordinate 3MC state rather than the 3MLCT state. The work therefore provides additional insights into the photophysical and photochemical properties of ruthenium triazole-containing complexes and their excited state dynamics

HighP–TNano-Mechanics of Polycrystalline Nickel

We have conducted highP–Tsynchrotron X-ray and time-of-flight neutron diffraction experiments as well as indentation measurements to study equation of state, constitutive properties, and hardness of nanocrystalline and bulk nickel. Our lattice volume–pressure data present a clear evidence of elastic softening in nanocrystalline Ni as compared with the bulk nickel. We show that the enhanced overall compressibility of nanocrystalline Ni is a consequence of the higher compressibility of the surface shell of Ni nanocrystals, which supports the results of molecular dynamics simulation and a generalized model of a nanocrystal with expanded surface layer. The analytical methods we developed based on the peak-profile of diffraction data allow us to identify “micro/local” yield due to high stress concentration at the grain-to-grain contacts and “macro/bulk” yield due to deviatoric stress over the entire sample. The graphic approach of our strain/stress analyses can also reveal the corresponding yield strength, grain crushing/growth, work hardening/softening, and thermal relaxation under highP–Tconditions, as well as the intrinsic residual/surface strains in the polycrystalline bulks. From micro-indentation measurements, we found that a low-temperature annealing (T < 0.4 Tm) hardens nanocrystalline Ni, leading to an inverse Hall–Petch relationship. We explain this abnormal Hall–Petch effect in terms of impurity segregation to the grain boundaries of the nanocrystalline Ni

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

A stronger acceptor decreases the rates of charge transfer:Ultrafast dynamics and on/off switching of charge separation in organometallic Donor-Bridge-Acceptor systems

To unravel the role of driving force and structural changes in directing the photoinduced pathways in donor–bridge–acceptor (DBA) systems, we compared the ultrafast dynamics in novel DBAs which share a phenothiazine (PTZ) electron donor and a Pt(II) trans-acetylide bridge (–C[triple bond, length as m-dash]C–Pt–C[triple bond, length as m-dash]C–), but bear different acceptors conjugated into the bridge (naphthalene-diimide, NDI; or naphthalene-monoimide, NAP). The excited state dynamics were elucidated by transient absorption, time-resolved infrared (TRIR, directly following electron density changes on the bridge/acceptor), and broadband fluorescence-upconversion (FLUP, directly following sub-picosecond intersystem crossing) spectroscopies, supported by TDDFT calculations. Direct conjugation of a strong acceptor into the bridge leads to switching of the lowest excited state from the intraligand 3IL state to the desired charge-separated 3CSS state. We observe two surprising effects of an increased strength of the acceptor in NDI vs. NAP: a ca. 70-fold slow-down of the 3CSS formation—(971 ps)−1 vs. (14 ps)−1, and a longer lifetime of the 3CSS (5.9 vs. 1 ns); these are attributed to differences in the driving force ΔGet, and to distance dependence. The 100-fold increase in the rate of intersystem crossing—to sub-500 fs—by the stronger acceptor highlights the role of delocalisation across the heavy-atom containing bridge in this process. The close proximity of several excited states allows one to control the yield of 3CSS from ∼100% to 0% by solvent polarity. The new DBAs offer a versatile platform for investigating the role of bridge vibrations as a tool to control excited state dynamics