Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues.

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date.

Tuning the photoactivated anticancer activity of Pt(iv) compounds distant ferrocene conjugation.

Photoactive prodrugs offer potential for spatially-selective antitumour activity with minimal effects on normal tissues. Excited-state chemistry can induce novel effects on biochemical pathways and combat resistance to conventional drugs. Photoactive metal complexes in particular, have a rich and relatively unexplored photochemistry, especially an ability to undergo facile intersystem crossing and populate triplet states.

Customising the plunge-freezing workflow for challenging conditions.

Grid freezing is a critical step for successful cryo-transmission electron microscopy, and optimising freezing conditions is a considerable bottleneck in many projects. To improve reproducibility in grid preparation, temperature- and humidity-controlled chambers were built into the second generation of plunge-freezers, including the ThermoFisherScientific Vitrobot and Leica GP. Since then, for most published structures, the proteins were plunge-frozen from a cold, humid environment.

Biogenic metallic elements in the human brain?

The chemistry of copper and iron plays a critical role in normal brain function. A variety of enzymes and proteins containing positively charged Cu, Cu, Fe, and Fe control key processes, catalyzing oxidative metabolism and neurotransmitter and neuropeptide production. Here, we report the discovery of elemental (zero-oxidation state) metallic Cu accompanying ferromagnetic elemental Fe in the human brain.

Does deamidation affect inhibitory mechanisms towards amyloid protein aggregation?

Deamidated amyloid proteins have been shown to accelerate fibril formation. Herein, the results show the inhibition performance and the interaction site between site-specific inhibitor and amyloid protein are significantly influenced by deamidation; while the inhibition mechanism of non-site specific inhibitor shows no significant disruption caused by amyloid protein deamidation.

X-ray tomography of cryopreserved human prostate cancer cells: mitochondrial targeting by an organoiridium photosensitiser.

The organoiridium complex Ir[(C,N)(O,O)] (1) where C, N = 1-phenylisoquinoline and O,O = 2,2,6,6-tetramethyl-3,5-heptanedionate is a promising photosensitiser for Photo-Dynamic Therapy (PDT). 1 is not toxic to cells in the dark. However, irradiation of the compound with one-photon blue or two-photon red light generates high levels of singlet oxygen (O) (in Zhang et al.

Biotinylated photoactive Pt(iv) anticancer complexes.

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)(N)(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.

Determination of the Aggregate Binding Site of Amyloid Protofibrils Using Electron Capture Dissociation Tandem Mass Spectrometry.

Amyloid fibril formation is a hallmark in a range of human diseases. Analysis of the molecular details of amyloid aggregation, however, is limited by the difficulties in solubilizing, separating, and identifying the aggregated biomolecules. Additional labeling or protein modification is required in many current analytical techniques in order to provide molecular details of amyloid protein aggregation, but these modifications may result in protein structure disruption.

Does deamidation of islet amyloid polypeptide accelerate amyloid fibril formation?

Mass spectrometry has been applied to determine the deamidation sites and the aggregation region of the deamidated human islet amyloid polypeptide (hIAPP). Mutant hIAPP with iso-aspartic residue mutations at possible deamidation sites showed very different fibril formation behaviour, which correlates with the observed deamidation-induced acceleration of hIAPP aggregation.

Biguanide Iridium(III) Complexes with Potent Antimicrobial Activity.

We have synthesized novel organoiridium(III) antimicrobial complexes containing a chelated biguanide, including the antidiabetic drug metformin. These 16- and 18-electron complexes were characterized by NMR, ESI-MS, elemental analysis, and X-ray crystallography. Several of these complexes exhibit potent activity against Gram-negative bacteria and Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus (MRSA)) and high antifungal potency toward C.

Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer's disease subjects.

Altered metabolism of biometals in the brain is a key feature of Alzheimer's disease, and biometal interactions with amyloid-β are linked to amyloid plaque formation. Iron-rich aggregates, including evidence for the mixed-valence iron oxide magnetite, are associated with amyloid plaques. To test the hypothesis that increased chemical reduction of iron, as observed in vitro in the presence of aggregating amyloid-β, may occur at sites of amyloid plaque formation in the human brain, the nanoscale distribution and physicochemical states of biometals, particularly iron, were characterised in isolated amyloid plaque cores from human Alzheimer's disease cases using synchrotron X-ray spectromicroscopy.

Histological Profiling Over Time to Optimize Root Cell Type-Specific Reporter Lines for Cell Sorting.

Cell type-specific marker lines expressing fluorophores such as GFP or GUS can be used as starting material from which single cell types can be isolated by fluorescence-activated cell sorting (FACS) and/or for the study of root development. Establishing the stability of these lines is an essential step prior to further study to ensure that marker expression and localization is stable over time and during environmental perturbations of interest to researchers applying these lines as treatments. Here, we detail the use of root cross sectioning to investigate marker expression throughout the length and width of the root using the model legume Medicago truncatula as an example.

Evaluation of the Antimicrobial Activity of Cationic Polymers against Mycobacteria: Toward Antitubercular Macromolecules.

Antimicrobial resistance is a global healthcare problem with a dwindling arsenal of usable drugs. Tuberculosis, caused by Mycobacterium tuberculosis, requires long-term combination therapy and multi- and totally drug resistant strains have emerged. This study reports the antibacterial activity of cationic polymers against mycobacteria, which are distinguished from other Gram-positive bacteria by their unique cell wall comprising a covalently linked mycolic acid-arabinogalactan-peptidoglycan complex (mAGP), interspersed with additional complex lipids which helps them persist in their host.

Synchrotron X-Ray Fluorescence Nanoprobe Reveals Target Sites for Organo-Osmium Complex in Human Ovarian Cancer Cells.

A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub-cellular distribution of [Os(η -p-cym)(Azpy-NMe )I] (p-cym=p-cymene, Azpy-NMe =2-(p-[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X-ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death.

Use of complementary nucleobase-containing synthetic polymers to prepare complex self-assembled morphologies in water.

Amphiphilic nucleobase-containing block copolymers with poly(oligo(ethylene glycol) methyl ether methacrylate) as the hydrophilic block and nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerization and then self-assembled solvent switch in aqueous solutions. Effects of the common solvent on the resultant morphologies of the adenine (A) and thymine (T) homopolymers, and A/T copolymer blocks and blends were investigated. These studies highlighted that depending on the identity of the common solvent, DMF or DMSO, spherical micelles or bicontinuous micelles were obtained.

Recyclable l-Proline Functional Nanoreactors with Temperature-Tuned Activity Based on Core-Shell Nanogels.

Recyclable core-shell (CS) nanogels based on l-proline-containing hydrophobic cores with a thermoresponsive poly(-isopropylacrylamide) (PNIPAM) shell have been synthesized via a seeded precipitation polymerization process. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to verify the successful addition of the shell and investigate the thermoresponsive properties of the nanostructures. The catalytic activity of the nanogels was assessed in a model asymmetric aldol reaction, where an enhancement was observed with increasing temperature, attributed to the hydrophobic nature of the PNIPAM shell.

Precious metal carborane polymer nanoparticles: characterisation of micellar formulations and anticancer activity.

We report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] ( and ) in Pluronic® triblock copolymer P123 core-shell micelles. The spherical nanoparticles and , dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively).

Morphotypes of virus-like particles in two hydrothermal vent fields on the East Scotia Ridge, Antarctica.

Viruses from extreme environments are still largely unexplored and may harbor unseen genetic potential. Here, we present a first glance at the morphological diversity of virus like particles (VLPs) from an environment that is extreme in more than one respect: two recently discovered hydrothermal vent fields on the East Scotia Ridge in the Southern Ocean near Antarctica. They are the southernmost hydrothermal sites found to date and have been shown to present a new biogeographic province, containing several new macrofaunal species and associated microbial organisms.

Fabrication of crystals from single metal atoms.

Metal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size.

Organometallic Iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis.

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (Ir(III)) complexes [Ir(Cp(x))(XY)Cl](+/0) (Cp(x) = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cp(x) ring. In comparison, highly potent complex 4 (Cp(x) = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze.