Structure-Property Relationships for Potential Inversion from Electron Acceptors Based on Thiophene-Fused Triptycene Quinones, 1,4-Diketones and their Malononitrile Adducts

The synthesis and properties of a series of 11,11,12,12-tetracyano-9,10-anthraquinodimethane (TCAQ) inspired electron acceptors based on thiophene-fused quinone and triptycene motifs is presented. This has yielded insights into structure-property relationships for establishing and modulating simultaneous two electron reduction processes in TCAQ analogues. These new compounds were synthesised using a Friedel-Crafts acylation between triptycene and thiophene-3,4-dicarbonyl chloride. Isomeric para-quinones featuring a [c]-fused thiophene on one side and a β,β- or α,β-fused triptycene on the other were isolated alongside a thiophene-3,4-diketone which bears two triptycene fragments. Knoevenagel condensation of these products with malononitrile produced a quinoidal bis(dicyanomethylene), an oxo-dicyanomethylene and an acyclic bis(dicyanomethylene). This series of new electron accepting molecules has been studied using X-ray crystallography and the implications of their 3D structures on NMR and UV/vis absorbance spectroscopy and cyclic voltammetry results have been ascertained with conclusions underpinned by computational methods

Elucidating the non-radiative losses encountered in intramolecular charge transfer compounds with benzodithiophene-4,8-dione acceptors

A new yellow-emitting quadrupolar donor-π-acceptor-π-donor (D-π-A-π-D) molecule compound has been synthesised featuring benzo-[1,2-c:4,5-c′]dithiophene-4,8-dione as the acceptor. This molecule was prepared for the purpose of elucidating the origins of the very low photoluminescence quantum yield encountered in its thermally activated delayed fluorescent (TADF) red-emitting isomer which used benzo-[1,2-b:4,5-b′]dithiophene-4,8-dione as the acceptor. The molecule was designed to circumvent the energy gap law, by having a wider HOMO-LUMO gap, while retaining a comparable singlet-triplet gap but ultimately demonstrates even weaker photoluminescence than the red isomer. It shows extremely fast intersystem crossing followed by rapid non-radiative decay and no observable TADF. The electronic structure of this new molecule has been studied using cyclic voltammatery alongside steady-state and transient optical spectroscopy, with observations underpinned by computational insights. To identify whether the observations made from the experimental results might be general properties of benzodithiophene-4,8-dione containing emitters, a computational study is extended to the four isomers of benzodithiophene-4,8-dione in comparison with 9,10-anthraquinone. The results suggest that the singlet and triplet manifolds of these systems are strongly coupled via spin-orbit interactions, and explain how the relative electron-accepting strength of these quinones arises from an interplay between the resonance gains or losses of the central benzene and fused thiophene rings upon photoexcitation. This provides valuable insights into the design principles required for efficient organic light-emitting materials.</p

Identification of Burkholderia pseudomallei Near-Neighbor Species in the Northern Territory of Australia

Identification and characterization of near-neighbor species are critical to the development of robust molecular diagnostic tools for biothreat agents. One such agent, Burkholderia pseudomallei, a soil bacterium and the causative agent of melioidosis, is lacking in this area because of its genomic diversity and widespread geographic distribution. The Burkholderia genus contains over 60 species and occupies a large range of environments including soil, plants, rhizospheres, water, animals and humans. The identification of novel species in new locations necessitates the need to identify the true global distribution of Burkholderia species, especially the members that are closely related to B. pseudomallei. In our current study, we used the Burkholderia-specific recA sequencing assay to analyze environmental samples from the Darwin region in the Northern Territory of Australia where melioidosis is endemic. Burkholderia recA PCR negative samples were further characterized using 16s rRNA sequencing for species identification. Phylogenetic analysis demonstrated that over 70% of the bacterial isolates were identified as B. ubonensis indicating that this species is common in the soil where B. pseudomallei is endemic. Bayesian phylogenetic analysis reveals many novel branches within the B. cepacia complex, one novel B. oklahomensis-like species, and one novel branch containing one isolate that is distinct from all other samples on the phylogenetic tree. During the analysis with recA sequencing, we discovered 2 single nucleotide polymorphisms in the reverse priming region of B. oklahomensis. A degenerate primer was developed and is proposed for future use. We conclude that the recA sequencing technique is an effective tool to classify Burkholderia and identify soil organisms in a melioidosis endemic area

The Genetic and Molecular Basis of O-Antigenic Diversity in Burkholderia pseudomallei Lipopolysaccharide

Lipopolysaccharide (LPS) is one of the most important virulence and antigenic components of Burkholderia pseudomallei, the causative agent of melioidosis. LPS diversity in B. pseudomallei has been described as typical, atypical or rough, based upon banding patterns on SDS-PAGE. Here, we studied the genetic and molecular basis of these phenotypic differences. Bioinformatics was used to determine the diversity of genes known or predicted to be involved in biosynthesis of the O-antigenic moiety of LPS in B. pseudomallei and its near-relative species. Multiplex-PCR assays were developed to target diversity of the O-antigen biosynthesis gene patterns or LPS genotypes in B. pseudomallei populations. We found that the typical LPS genotype (LPS genotype A) was highly prevalent in strains from Thailand and other countries in Southeast Asia, whereas the atypical LPS genotype (LPS genotype B) was most often detected in Australian strains (∼13.8%). In addition, we report a novel LPS ladder pattern, a derivative of the atypical LPS phenotype, associated with an uncommon O-antigen biosynthesis gene cluster that is found in only a small B. pseudomallei sub-population. This new LPS group was designated as genotype B2. We also report natural mutations in the O-antigen biosynthesis genes that potentially cause the rough LPS phenotype. We postulate that the diversity of LPS may correlate with differential immunopathogenicity and virulence among B. pseudomallei strains

Diversity of 16S-23S rDNA Internal Transcribed Spacer (ITS) Reveals Phylogenetic Relationships in Burkholderia pseudomallei and Its Near-Neighbors

Length polymorphisms within the 16S-23S ribosomal DNA internal transcribed spacer (ITS) have been described as stable genetic markers for studying bacterial phylogenetics. In this study, we used these genetic markers to investigate phylogenetic relationships in Burkholderia pseudomallei and its near-relative species. B. pseudomallei is known as one of the most genetically recombined bacterial species. In silico analysis of multiple B. pseudomallei genomes revealed approximately four homologous rRNA operons and ITS length polymorphisms therein. We characterized ITS distribution using PCR and analyzed via a high-throughput capillary electrophoresis in 1,191 B. pseudomallei strains. Three major ITS types were identified, two of which were commonly found in most B. pseudomallei strains from the endemic areas, whereas the third one was significantly correlated with worldwide sporadic strains. Interestingly, mixtures of the two common ITS types were observed within the same strains, and at a greater incidence in Thailand than Australia suggesting that genetic recombination causes the ITS variation within species, with greater recombination frequency in Thailand. In addition, the B. mallei ITS type was common to B. pseudomallei, providing further support that B. mallei is a clone of B. pseudomallei. Other B. pseudomallei near-neighbors possessed unique and monomorphic ITS types. Our data shed light on evolutionary patterns of B. pseudomallei and its near relative species

Gene-Based Analysis of Regionally Enriched Cortical Genes in GWAS Data Sets of Cognitive Traits and Psychiatric Disorders

Background: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked. Principal Findings: At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample. Conclusion: Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits

The Man Who Mistook His Neuropsychologist For a Popstar: When Configural Processing Fails in Acquired Prosopagnosia

We report the case of an individual with acquired prosopagnosia who experiences extreme difficulties in recognising familiar faces in everyday life despite excellent object recognition skills. Formal testing indicates that he is also severely impaired at remembering pre-experimentally unfamiliar faces and that he takes an extremely long time to identify famous faces and to match unfamiliar faces. Nevertheless, he performs as accurately and quickly as controls at identifying inverted familiar and unfamiliar faces and can recognise famous faces from their external features. He also performs as accurately as controls at recognising famous faces when fracturing conceals the configural information in the face. He shows evidence of impaired global processing but normal local processing of Navon figures. This case appears to reflect the clearest example yet of an acquired prosopagnosic patient whose familiar face recognition deficit is caused by a severe configural processing deficit in the absence of any problems in featural processing. These preserved featural skills together with apparently intact visual imagery for faces allow him to identify a surprisingly large number of famous faces when unlimited time is available. The theoretical implications of this pattern of performance for understanding the nature of acquired prosopagnosia are discussed

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms