Clustering and Halogen Effects Enabled Red/Near-Infrared Room Temperature Phosphorescence from Aliphatic Cyclic Imides

<a>Pure organics with room temperature phosphorescence (RTP) are urgently demanded in advanced optoelectronic and bioelectronic applications. However, currently reported phosphors are mostly aromatics and restricted to blue to orange colors. It remains an enormous challenge to achieve red and near-infrared (NIR) RTP, particularly for those from nonaromatics. Here we demonstrate a series of cyclic imides derived from succinimide, which can emit red (665, 690 nm) and even NIR (745 nm) RTP with outstanding efficiencies of up to 9.2%, despite their rather limited molecular conjugations. Such unique emission should be ascribed to the presence of the imide unit and heavy atoms, effective molecular clustering, and the electron delocalization of halogens, which not only greatly facilitate intersystem crossing, but also afford significantly extended through-space conjugation and rigidified conformations.</a> These results pave the way to the rational construction of red and NIR nonconventional luminophores through synergistic clustering and halogen effects.

OP0038 SPLICEOSOME ALTERATIONS IN LEUCOCYTES FROM APS, SLE AND SLE+APS PATIENTS ARE CLOSELY RELATED TO THEIR MAIN CLINICAL FEATURES

Background:To date, although multiple molecular approaches have illustrated the various aspects of Primary Antiphospholipid Syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome plus lupus (APS plus SLE), no study has so far fully characterized the potential role of posttranscriptional regulatory mechanisms such as the alternative splicing.Objectives:To identify shared and differential changes in the splicing machinery of immune cells from APS, SLE and APS plus SLE patients, and their involvement in the activity and clinical profile of these autoimmune disorders.Methods:Monocytes, lymphocytes and neutrophils from 80 patients (22 APS, 35 SLE and 23 APS plus SLE) and 50 healthy donors (HD) were purified by immunomagnetic selection. Then, selected elements of the splicing machinery were evaluated using a microfluidic qPCR array (Fluidigm). In parallel, extensive clinical/serological evaluation was performed, comprising disease activity, thrombosis and renal involvement, along with autoantibodies, acute phase reactants, complement and inflammatory molecules. Molecular clustering analyses and correlation/association studies were developed.Results:Patients with primary APS, SLE and APS plus SLE displayed significant and specific alterations in the splicing machinery components in comparison with HD, that were further specific for each leukocyte subset. Besides, these alterations were associated with distinctive clinical features.Hence, in APS, clustering analysis allowed to identify two sets of patients representing different molecular profile groups with respect to the expression levels of splicing machinery components. Principal component analyses confirmed a clear separation between patients. Clinically, cluster 1 characterized patients with higher thrombotic episodes and recurrences than cluster 2 and displayed a higher adjusted global APS score (aGAPSS). Accordingly, these patients showed higher levels of inflammatory mediators than cluster 2.Similarly, in patients with APS plus SLE, clustering analysis allowed to identify two sets of patients showing differential expression of splicing machinery components. Clinical and laboratory profiles showed that cluster 2 characterized patients that had suffered more thrombotic recurrences, most of them displaying an aGAPSS over 12 points and expressing higher levels of inflammatory mediators than cluster 1. The incidence of lupus nephropathy was similarly represented in both clusters.Lastly, in SLE patients, molecular clustering analysis identified two sets of patients showing distinctive clinical features. One cluster characterized most of the patients positive for anti-dsDNA antibodies, further suffering lupus nephropathy, and a high proportion of them also presenting atheroma plaques and high levels of inflammatory mediators.Correlation studies further demonstrated that several deranged splicing machinery components in immune cells (i.e. SF3B1tv1, PTBP1, PRP8 and RBM17) were linked to the autoimmune profile of the three autoimmune diseases, albeit in a specific way on each disorder. Accordingly, in vitro treatment of HD lymphocytes with aPL-IgG or anti-dsDNA-IgG changed the expression of spliceosome components also found altered in vivo in the three autoimmune diseases. Finally, the induced over/downregulated expression of selected spliceosome components in leukocytes modulated the expression of inflammatory cytokines, changed the procoagulant/adhesion activities of monocytes and regulated NETosis in neutrophils.Conclusion:1) The splicing machinery, profoundly altered in leukocytes from APS, APS plus SLE and SLE patients, is closely related to the activity of these diseases, their autoimmune and inflammatory profiles. 2) The analysis of the splicing machinery allows the segregation of APS, APS plus SLE and SLE, with specific components explaining the CV risk and renal involvement in these highly related autoimmune disorders.Acknowledgements:Funded by ISCIII, PI18/00837 and RIER RD16/0012/0015 co-funded with FEDERDisclosure of Interests:None declared

Clustering and Halogen Effects Enabled Red/Near-Infrared Room Temperature Phosphorescence from Aliphatic Cyclic Imides

<a>Pure organics with room temperature phosphorescence (RTP) are urgently demanded in advanced optoelectronic and bioelectronic applications. However, currently reported phosphors are mostly aromatics and restricted to blue to orange colors. It remains an enormous challenge to achieve red and near-infrared (NIR) RTP, particularly for those from nonaromatics. Here we demonstrate a series of cyclic imides derived from succinimide, which can emit red (665, 690 nm) and even NIR (745 nm) RTP with outstanding efficiencies of up to 9.2%, despite their rather limited molecular conjugations. Such unique emission should be ascribed to the presence of the imide unit and heavy atoms, effective molecular clustering, and the electron delocalization of halogens, which not only greatly facilitate intersystem crossing, but also afford significantly extended through-space conjugation and rigidified conformations.</a> These results pave the way to the rational construction of red and NIR nonconventional luminophores through synergistic clustering and halogen effects.

Clustering and Halogen Effects Enabled Red/Near-Infrared Room Temperature Phosphorescence from Aliphatic Cyclic Imides

<a>Pure organics with room temperature phosphorescence (RTP) are urgently demanded in advanced optoelectronic and bioelectronic applications. However, currently reported phosphors are mostly aromatics and restricted to blue to orange colors. It remains an enormous challenge to achieve red and near-infrared (NIR) RTP, particularly for those from nonaromatics. Here we demonstrate a series of cyclic imides derived from succinimide, which can emit red (665, 690 nm) and even NIR (745 nm) RTP with outstanding efficiencies of up to 9.2%, despite their rather limited molecular conjugations. Such unique emission should be ascribed to the presence of the imide unit and heavy atoms, effective molecular clustering, and the electron delocalization of halogens, which not only greatly facilitate intersystem crossing, but also afford significantly extended through-space conjugation and rigidified conformations.</a> These results pave the way to the rational construction of red and NIR nonconventional luminophores through synergistic clustering and halogen effects.

Genetic structure in natural populations of Dacrydium elatum (Roxb.) Wall. (Podocarpaceae) in the Central Highlands of Vietnam inferred by Microsatellites

To provide a reference for the conservation and application of breeding parentallines resource of Dacrydium elatum (Roxb.). Genetic diversity and population structure of eighty individuals from four populations (Kon Tum, Gia Lai, Dak Lak and Lam Dong) in Central Highlands were evaluated using eight SSR markers. Based on the SSR data, 21 alleles were detected by eight SSR with high polymorphism. The genetic diversity of levels within the populations were moderately high (Ho = 0.555, He = 0.429). The average number of shannon information index were 0.618 and genetic differentiation among populations was low (Fst=0.097). The AMOVA revealed high genetic variation within individuals (87%) compared among populations (13%). The UPGMA phenogram showed that the results of molecular clustering largely agreed with the pedigree and geographic origin. Three populations (NL, KCR and BDNB) were clustered together and CYS population was separated. The maximum quantity ΔK was observed for K=2 in population structure analysis, indicating that the entire collection could be divided into two main groups of genes. This study can provide a theoretical basis for genetic resource management and varieties identification of D. elatum resources, and provide reference basis for breeding.

Kinetic effects of molecular clustering and solvation by extended networks in zeolite acid catalysis

“Solvent effects” at interfaces in heterogeneous catalysts are described by transition state theory treatments that identify kinetic regimes associated with molecular clustering and the solvation of such clusters by extended molecular networks.

Unscrambling fluorophore blinking for comprehensive cluster detection via photoactivated localization microscopy

Determining nanoscale protein distribution via Photoactivated Localization Microscopy (PALM) mandates precise knowledge of the applied fluorophore’s blinking properties to counteract overcounting artifacts that distort the resulting biomolecular distributions. Here, we present a readily applicable methodology to determine, optimize and quantitatively account for the blinking behavior of any PALM-compatible fluorophore. Using a custom-designed platform, we reveal complex blinking of two photoswitchable fluorescence proteins (PS-CFP2 and mEOS3.2) and two photoactivatable organic fluorophores (PA Janelia Fluor 549 and Abberior CAGE 635) with blinking cycles on time scales of several seconds. Incorporating such detailed information in our simulation-based analysis package allows for robust evaluation of molecular clustering based on individually recorded single molecule localization maps.

A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

SUMMARYBRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily-conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionising radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.