抗精神病薬によるジストニアの発現機序に関する実験的研究 σ (sigma) sites の関与について

Published ErratumBurkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.Wellcome Trus

Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of “long COVID-19”, and defines key cells and cytokines that delineate true and quasi-convalescent states

Modification of triphenylphosphonium lipophilic cations for mitochondrial delivery

Triphenylphosphonium (TPP+) moieties, when conjugated to a molecule of interest, results in greater mitochondrial accumulation relative to the unconjugated cargo. However, while TPP+ moieties are known to be effective at conferring mitochondrial-targeting abilities to molecules, modifications to the structure of the TPP+ moiety itself is relatively rare. Instead, the key modifications employed to tune molecular properties is by altering the structure of the linker, rather than the phosphine used. However, the lack of controlled studies comparing the two contrasting methodologies impedes the general adoption of modified TPP+ as mitochondrial vectors. In addition, the functionalization of TPP+ has been mostly limited to the incorporation of simple functional groups into the TPP+ moiety. In light of these issues, there is a pressing need for both systematic studies on the topic, as well as the development of novel TPP+ species. In this work, we synthesized modified triphenylphosphonium moieties, examined its effects on steric and electronic properties, as well as its corresponding effect on mitochondrial delivery.Doctor of Philosoph

Intellectual capital and its increasing relevance.

This project examines the effect of three factors -- information intensity of industry, number of employees and Internet capabilities -- on the value of Intellectual Capital. Three hypotheses were formulated and tested using financial data collected from a sample of 136 organisations. The results show that Intellectual Capital value is higher in high information intensity companies and that organisations should be aware of the importance of human capital to the intangible value of the firm

Size-control in the synthesis of oxo-bridged phosphazane macrocycles via a modular addition approach

Inorganic macrocycles remain largely underdeveloped compared with their organic counterparts due to the challenges involved in their synthesis. Among them, cyclodiphosphazane macrocycles have shown to be promising candidates for supramolecular chemistry applications due to their ability to encapsulate small molecules or ions within their cavities. However, further developments have been handicapped by the lack of synthetic routes to high-order cyclodiphosphazane macrocycles. Moreover, current approaches allow little control over the size of the macrocycles formed. Here we report the synthesis of high-order oxygen-bridged phosphazane macrocycles via a “3 + n cyclisation” (n = 1 and 3). Using this method, an all-PIII high-order hexameric cyclodiphosphazane macrocycle was isolated, displaying a larger macrocyclic cavity than comparable organic crown-ethers. Our approach demonstrates that increasing building block complexity enables precise control over macrocycle size, which will not only generate future developments in both the phosphazane and main group chemistry but also in the fields of supramolecular chemistry.Agency for Science, Technology and Research (A*STAR)Nanyang Technological UniversityPublished versionFG acknowledge A*STAR AME IRG (A1783c0003, and A2083c0050) and a NTU startup grant (M4080552) for financial support. F.L. thanks A*STAR for PR fellowship

Alkyl vs Aryl Modifications: A Comparative Study on Modular Modifications of Triphenylphosphonium Mitochondrial Vectors

Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provides further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications<br /

Beyond the TPP+ "gold standard": a new generation mitochondrial delivery vector based on extended PN frameworks

Mitochondrial targeting represents an attractive strategy for treating metabolic, degenerative and hyperproliferative diseases, since this organelle plays key roles in essential cellular functions. Triphenylphosphonium (TPP+) moieties - the current "gold standard" - have been widely used as mitochondrial targeting vectors for a wide range of molecular cargo. Recently, further optimisation of the TPP+ platform drew considerable interest as a way to enhance mitochondrial therapies. However, although the modification of this system appears promising, the core structure of the TPP+ moiety remains largely unchanged. Thus, this study explored the use of aminophosphonium (PN+) and phosphazenylphosphonium (PPN+) main group frameworks as novel mitochondrial delivery vectors. The PPN+ moiety was found to be a highly promising platform for this purpose, owing to its unique electronic properties and high lipophilicity. This has been demonstrated by the high mitochondrial accumulation of a PPN+-conjugated fluorophore relative to its TPP+-conjugated counterpart, and has been further supported by density functional theory and molecular dynamics calculations, highlighting the PPN+ moiety's unusual electronic properties. These results demonstrate the potential of novel phosphorus-nitrogen based frameworks as highly effective mitochondrial delivery vectors over traditional TPP+ vectors.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Nanyang Technological UniversityPublished versionF. G. would like to thank A*STAR AME IRG (A1783c0003 and A2083c0050), NTU for a start-up grant (M4080552) and MOE Tier 1 grants (RG 11/15 and RG 113/16) for financial support. F. G. also thanks the support of Fundaci´on para el Fomento en Asturias de la Investigaci´on Cient´ıfca Aplicada y la Tecnolog´ıa (FICYT) through the Margarita Salas Senior Program (AYUD/ 2021/59709) and the Ministerio de Ciencia e Innovaci´on through the project PID2021-127407NB-I00. F. G. would like to thank Monash University for affiliate position. We would like to also thank Nanyang Technological University for technical support. H. C. O. would like to thank NTU for NPGS scholarship. J. T. S. C., M. J. R. and P. A. F. acknowledge financial support from the Associate Laboratory for Green Chemistry Unit – LAQV@REQUIMTE, which received financial support from PT national funds (FCT/MCTES, Fundaç˜ao para a Ciˆencia e Tecnologia and Minist´erio da Ciˆencia, Tecnologia e Ensino Superior) through the project UIDB/50006/2020 j UIDP/50006/2020. J. T. S. C. thanks FCT for funding through the Individual Call to Scientific Employment Stimulus (CEECIND/01374/2018). All publication charges for this article have been paid for by the Royal Society of Chemistry

Phosphazenylphosphonium Frameworks: A Novel Main Group Mitochondrial Delivery Vector with Enhanced Properties

Mitochondrial targeting represents an attractive strategy for treating metabolic, degenerative and hyperproliferative diseases, since this organelle plays key roles in essential cellular functions. Triphenylphosphonium (TPP+) moieties – the current “gold standard” – have been widely used as mitochondrial targeting vectors for a wide range of molecular cargo. Recently, further optimisation of the TPP+ platform drew considerable interest as a way to enhance mitochondrial therapies. However, although the modification of this system appears promising, the core structure of the TPP+ moiety remains largely unchanged. Thus, in this study, we explored the use of aminophosphonium (PN+) and phosphazenylphosphonium (PPN+) main group frameworks as novel mitochondrial delivery vectors. The PPN+ moiety was found to be a highly promising platform for this purpose, owing to its unique electronic properties and high lipophilicity. This has been demonstrated by the high mitochondrial accumulation of a PPN+-conjugated fluorophore relative to its TPP+-conjugated counterpart, and has been further supported by density functional theory and molecular dynamics calculations, highlighting the PPN+ moiety’s unusual electronic properties. These results demonstrate the potential of novel phosphorus-nitrogen based frameworks as highly effective mitochondrial delivery vectors over traditional TPP+ vector