Real-time observation of multiexcitonic states in ultrafast singlet fission using coherent 2D electronic spectroscopy.

Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.237

Detection of subclinical keratoconus using biometric parameters

The validation of innovative methodologies for diagnosing keratoconus in its earliest stages is of major interest in ophthalmology. So far, subclinical keratoconus diagnosis has been made by combining several clinical criteria that allowed the definition of indices and decision trees, which proved to be valuable diagnostic tools. However, further improvements need to be made in order to reduce the risk of ectasia in patients who undergo corneal refractive surgery. The purpose of this work is to report a new subclinical keratoconus detection method based in the analysis of certain biometric parameters extracted from a custom 3D corneal model. This retrospective study includes two groups: the first composed of 67 patients with healthy eyes and normal vision, and the second composed of 24 patients with subclinical keratoconus and normal vision as well. The proposed detection method generates a 3D custom corneal model using computer-aided graphic design (CAGD) tools and corneal surfaces’ data provided by a corneal tomographer. Defined bio-geometric parameters are then derived from the model, and statistically analysed to detect any minimal corneal deformation. The metric which showed the highest area under the receiver-operator curve (ROC) was the posterior apex deviation. This new method detected differences between healthy and sub-clinical keratoconus corneas by using abnormal corneal topography and normal spectacle corrected vision, enabling an integrated tool that facilitates an easier diagnosis and follow-up of keratoconus.This publication has been carried out in the framework of the Thematic Network for Co-Operative Research in Health (RETICS) reference number RD16/0008/0012 financed by the Carlos III Health Institute-General Subdirection of Networks and Cooperative Investigation Centers (R&D&I National Plan 2013–2016) and the European Regional Development Fund (FEDER)

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes

UPF201 Archaeal Specific Family Members Reveal Structural Similarity to RNA-Binding Proteins but Low Likelihood for RNA-Binding Function

We have determined X-ray crystal structures of four members of an archaeal specific family of proteins of unknown function (UPF0201; Pfam classification: DUF54) to advance our understanding of the genetic repertoire of archaea. Despite low pairwise amino acid sequence identities (10–40%) and the absence of conserved sequence motifs, the three-dimensional structures of these proteins are remarkably similar to one another. Their common polypeptide chain fold, encompassing a five-stranded antiparallel β-sheet and five α-helices, proved to be quite unexpectedly similar to that of the RRM-type RNA-binding domain of the ribosomal L5 protein, which is responsible for binding the 5S- rRNA. Structure-based sequence alignments enabled construction of a phylogenetic tree relating UPF0201 family members to L5 ribosomal proteins and other structurally similar RNA binding proteins, thereby expanding our understanding of the evolutionary purview of the RRM superfamily. Analyses of the surfaces of these newly determined UPF0201 structures suggest that they probably do not function as RNA binding proteins, and that this domain specific family of proteins has acquired a novel function in archaebacteria, which awaits experimental elucidation

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Chronic stroke sensorimotor impairment is related to smaller hippocampal volumes: an ENIGMA analysis

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper‐limb sensorimotor impairment. We investigated associations between non‐lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross‐sectional T1‐weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta‐Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA‐UE (Fugl‐Meyer Assessment of Upper Extremity). Robust mixed‐effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni‐corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; β=0.16) but not contralesional (P=0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; β=−0.26) and contralesional (P=0.006; β=−0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; β=−0.21) and extent of sensorimotor damage (P=0.003; β=−0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402