Development, synthesis and anticancer evaluation of trinuclear Platinum Group Metal organometallic complexes

Over the past few decades metals in medicine have played to play a significant role, especially after the discovery of the anticancer properties of cisplatin. However, acquired and intrinsic resistance, toxicity and a host of side-effects have encouraged the research for new metal based anticancer agents. Organometallic complexes have proved to be successful anticancer agents and several have commenced clinical trials. The aim of this study was to prepare and characterize trinuclear platinum group organometallic complexes and investigate their in vitro activity. The first series of ester containing complexes were prepared. The ligands were generated by the preparation of Schiff base ligands obtained from the condensation of 4-aminophenylmethanol and either benzaldehyde, 2-pyridinecarboxaldehyde or salicylaldehyde. Trimeric ester ligands were prepared from these monomeric ligands by reaction with trimesoyl chloride

trans-Dichloridobis[dicyclo­hex­yl(phen­yl)phosphane-κP]palladium(II)

The title compound, [PdCl2{P(C6H11)2(C6H5)}2], forms a monomeric complex with a trans-square-planar geometry. The Pd—P bond lengths are 2.3343 (5) Å, as the Pd atom lies on an inversion centre, while the Pd—Cl bond lengths are 2.3017 (4) Å. The observed structure was found to be closely related to [PdCl2{P(C6H11)3}2] [Grushin et al. (1994 ▶). Inorg. Chem. 33, 4804–4806], [PdBr2{P(C6H11)3}2] [Clarke et al. (2003 ▶). Dalton Trans. pp. 4393–4394] and [PdCl2P(C6H11)2(C7H7)}2] [Vuoti et al. (2008 ▶). Eur. J. Inorg. Chem. pp. 397–407] (C6H11 is cyclo­hexyl and C7H7 is o-tol­yl). One of the cyclo­hexyl rings is disordered with the phenyl ring in a 0.587 (9):413 (9) ratio. Five long-range C—H⋯Cl inter­actions were observed within the structure

Triethyl­ammonium hexa-μ2-acetato-κ12 O:O′-diacetato-κ2 O-aqua-μ3-oxido-triferrate(III) toluene monosolvate

The title compound, (C6H16N)[Fe3(CH3CO2)8O(H2O)]·C7H8, was serendipitously crystallized from a reaction of disilanol with iron(II) acetate. The trinuclear acetatoferrate(III) anion has a triethyl­ammonium cation as the counterion. The three Fe atoms lie on the vertices of a regular triangle and are octa­hedrally coordinated. The complete coordination of the anion includes shared ligands among the three metal ions: a central tribridging O atom and six bidentate bridging acetyl groups. The six-coordinations of two of the metal ions are completed by a monodentate acetate ligand, whereas that of the third metal ion is completed by a water mol­ecule. The uncoordinated triethyl­ammonium cation is involved in N—H⋯O hydrogen bonding to a singly coordinated acetyl group. The coordinated aqua mol­ecule is involved in bifurcated O—H⋯O hydrogen bonding. C—H⋯O inter­actions are also observed. The toluene solvent molecule is disordered over two sets of sites in a 0.609 (11):0.391 (11) ratio

trans-Carbonylchloridobis[tris(4-chlorophenyl) phosphane]rhodium(I) acetone monosolvate

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Immunobiology of a rationally-designed AAV2 capsid following intravitreal delivery in mice

Adeno-associated virus serotype 2 (AAV2) is a viral vector that can be used to deliver therapeutic genes to diseased cells in the retina. One strategy for altering AAV2 vectors involves the mutation of phosphodegron residues, which are thought to be phosphorylated/ubiquitinated in the cytosol, facilitating degradation of the vector and the inhibition of transduction. As such, mutation of phosphodegron residues have been correlated with increased transduction of target cells, however, an assessment of the immunobiology of wild-type and phosphodegron mutant AAV2 vectors following intravitreal (IVT) delivery to immunocompetent animals is lacking in the current literature. In this study, we show that IVT of a triple phosphodegron mutant AAV2 capsid is associated with higher levels of humoral immune activation, infiltration of CD4 and CD8 T-cells into the retina, generation of splenic germinal centre reactions, activation of conventional dendritic cell subsets, and elevated retinal gliosis compared to wild-type AAV2 capsids. However, we did not detect significant changes in electroretinography arising after vector administration. We also demonstrate that the triple AAV2 mutant capsid is less susceptible to neutralisation by soluble heparan sulphate and anti-AAV2 neutralising antibodies, highlighting a possible utility for the vector in terms of circumventing pre-existing humoral immunity. In summary, the present study highlights novel aspects of rationally-designed vector immunobiology, which may be relevant to their application in preclinical and clinical settings

Bis(dicyclo­hexyl­phenyl­phosphine)silver(I) nitrate

The title compound, [Ag(C18H27P)2]NO3, is a mononuclear salt species in which the Ag atom is coordinated by two phosphine ligands, forming a cation, with the nitrate as the counter-anion, weakly inter­acting with the Ag atom, resulting in Ag⋯O distances of 2.602 (6) and 2.679 (6) Å. The cationic silver–phosphine complex has a non-linear geometry in which the P—Ag—P angle is 154.662 (19)°. The Ag—P bond lengths are 2.4303 (6) and 2.4046 (5) Å

Primary ciliary dyskinesia with normal ultrastructure:three-dimensional tomography detects absence of DNAH11

In primary ciliary dyskinesia (PCD), motile ciliary dysfunction arises from ciliary defects usually confirmed by transmission electron microscopy (TEM). In 30% of patients, such as those with DNAH11 mutations, apparently normal ultrastructure makes diagnosis difficult. Genetic analysis supports diagnosis, but may not identify definitive causal variants. Electron tomography, an extension of TEM, produces three-dimensional ultrastructural ciliary models with superior resolution to TEM. Our hypothesis is that tomography using existing patient samples will enable visualisation of DNAH11-associated ultrastructural defects. Dual axis tomograms from araldite-embedded nasal cilia were collected in 13 PCD patients with normal ultrastructure (DNAH11 n=7, HYDIN n=2, CCDC65 n=3 and DRC1 n=1) and six healthy controls, then analysed using IMOD and Chimera software. DNAH11 protein is localised to the proximal ciliary region. Within this region, electron tomography indicated a deficiency of >25% of proximal outer dynein arm volume in all patients with DNAH11 mutations (n=7) compared to other patients with PCD and normal ultrastructure (n=6) and healthy controls (n=6). DNAH11 mutations cause a shared abnormality in ciliary ultrastructure previously undetectable by TEM. Advantageously, electron tomography can be used on existing diagnostic samples and establishes a structural abnormality where ultrastructural studies were previously normal

Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon‐induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS‐CoV‐2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS‐CoV‐2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS‐CoV‐2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS‐CoV‐2 and highlight the multiple distinct mechanisms by which SARS‐CoV‐2 subverts tetherin function

Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization

Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes

Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.</p