Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease

The dominant hypothesis of Alzheimer’s disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.This work was supported by the Boyarsky family, Battersby family, David King and family

Charge Photoinjection in Intercalated and Covalently Bound [Re(CO)_(3)(dppz)(py)]^(+)–DNA Constructs Monitored by Time-Resolved Visible and Infrared Spectroscopy

The complex [Re(CO)_(3)(dppz)(py′-OR)]+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine; py′-OR = 4-functionalized pyridine) offers IR sensitivity and can oxidize DNA directly from the excited state, making it a promising probe for the study of DNA-mediated charge transport (CT). The behavior of several covalent and noncovalent Re–DNA constructs was monitored by time-resolved IR (TRIR) and UV/visible spectroscopies, as well as biochemical methods, confirming the long-range oxidation of DNA by the excited complex. Optical excitation of the complex leads to population of MLCT and at least two distinct intraligand states. Experimental observations that are consistent with charge injection from these excited states include similarity between long-time TRIR spectra and the reduced state spectrum observed by spectroelectrochemistry, the appearance of a guanine radical signal in TRIR spectra, and the eventual formation of permanent guanine oxidation products. The majority of reactivity occurs on the ultrafast time scale, although processes dependent on slower conformational motions of DNA, such as the accumulation of oxidative damage at guanine, are also observed. The ability to measure events on such disparate time scales, its superior selectivity in comparison to other spectroscopic techniques, and the ability to simultaneously monitor carbonyl ligand and DNA IR absorption bands make TRIR a valuable tool for the study of CT in DNA

Mapping the multi-step mechanism of a photoredox catalyzed atom-transfer radical polymerization reaction by direct observation of the reactive intermediates

The rapid development of new applications of photoredox catalysis has so far outpaced the mechanistic studies important for rational design of new classes of catalysts. Here, we report the use of ultrafast transient absorption spectroscopic methods to reveal both mechanistic and kinetic details of multiple sequential steps involved in an organocatalyzed atom transfer radical polymerization reaction. The polymerization system studied involves a N,N-diaryl dihydrophenazine photocatalyst, a radical initiator (methyl 2-bromopropionate) and a monomer (isoprene). Time-resolved spectroscopic measurements spanning sub-picosecond to microseconds (i.e., almost 8 orders of magnitude of time) track the formation and loss of key reactive intermediates. These measurements identify both the excited state of the photocatalyst responsible for electron transfer and the radical intermediates participating in propagation reactions, as well as quantifying their lifetimes. The outcomes connect the properties of N,N-diaryl dihydrophenazine organic photocatalysts with the rates of sequential steps in the catalytic cycle

Ultrafast Excited-State Dynamics of Rhenium(I) Photosensitizers [Re(Cl)(CO)_(3)(N,N)] and [Re(imidazole)(CO)_(3)(N,N)]^+: Diimine Effects

Femto- to picosecond excited-state dynamics of the complexes [Re(L)(CO)_(3)(N,N)]^n (N,N = bpy, phen, 4,7-dimethyl-phen (dmp); L = Cl, n = 0; L = imidazole, n = 1+) were investigated using fluorescence up-conversion, transient absorption in the 650−285 nm range (using broad-band UV probe pulses around 300 nm) and picosecond time-resolved IR (TRIR) spectroscopy in the region of CO stretching vibrations. Optically populated singlet charge-transfer (CT) state(s) undergo femtosecond intersystem crossing to at least two hot triplet states with a rate that is faster in Cl (~100 fs)^(−1) than in imidazole (~150 fs)^(−1) complexes but essentially independent of the N,N ligand. TRIR spectra indicate the presence of two long-lived triplet states that are populated simultaneously and equilibrate in a few picoseconds. The minor state accounts for less than 20% of the relaxed excited population. UV−vis transient spectra were assigned using open-shell time-dependent density functional theory calculations on the lowest triplet CT state. Visible excited-state absorption originates mostly from mixed L;N,N^(•−) → Re^(II) ligand-to-metal CT transitions. Excited bpy complexes show the characteristic sharp near-UV band (Cl, 373 nm; imH, 365 nm) due to two predominantly ππ*(bpy^(•−)) transitions. For phen and dmp, the UV excited-state absorption occurs at 305 nm, originating from a series of mixed ππ* and Re → CO;N,N•− MLCT transitions. UV−vis transient absorption features exhibit small intensity- and band-shape changes occurring with several lifetimes in the 1−5 ps range, while TRIR bands show small intensity changes (≤5 ps) and shifts (~1 and 6−10 ps) to higher wavenumbers. These spectral changes are attributable to convoluted electronic and vibrational relaxation steps and equilibration between the two lowest triplets. Still slower changes (≥15 ps), manifested mostly by the excited-state UV band, probably involve local-solvent restructuring. Implications of the observed excited-state behavior for the development and use of Re-based sensitizers and probes are discussed

Development of a defined compost system for the study of plant-microbe interactions

Plant growth promoting rhizobacteria can improve plant health by providing enhanced nutrition, disease suppression and abiotic stress resistance, and have potential to contribute to sustainable agriculture. We have developed a sphagnum peat-based compost platform for investigating plant-microbe interactions. The chemical, physical and biological status of the system can be manipulated to understand the relative importance of these factors for plant health, demonstrated using three case studies: 1. Nutrient depleted compost retained its structure, but plants grown in this medium were severely stunted in growth due to removal of essential soluble nutrients - particularly, nitrogen, phosphorus and potassium. Compost nutrient status was replenished with the addition of selected soluble nutrients, validated by plant biomass; 2. When comparing milled and unmilled compost, we found nutrient status to be more important than matrix structure for plant growth; 3. In compost deficient in soluble P, supplemented with an insoluble inorganic form of P (Ca3(PO4)2), application of a phosphate solubilising Pseudomonas strain to plant roots provides a significant growth boost when compared with a Pseudomonas strain incapable of solubilising Ca3(PO4)2. Our findings show that the compost system can be manipulated to impose biotic and abiotic stresses for testing how microbial inoculants influence plant growth

Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function

Investigating interfacial electron transfer in dye-sensitized NiO using vibrational spectroscopy

Understanding what influences the formation and lifetime of charge-separated states is key to developing photoelectrochemical devices. This paper describes the use of time-resolved infrared absorption spectroscopy (TRIR) to determine the structure and lifetime of the intermediates formed on photoexcitation of two organic donor–π–acceptor dyes adsorbed to the surface of NiO. The donor and π-linker of both dyes is triphenylamine and thiophene but the acceptors differ, maleonitrile (1) and bodipy (2). Despite their structural similarities, dye 1 outperforms 2 significantly in devices. Strong transient bands in the fingerprint region (1 and 2) and nitrile region (2300–2000 cm−1) for 1 enabled us to monitor the structure of the excited states in solution or adsorbed on NiO (in the absence and presence of electrolyte) and the corresponding kinetics, which are on a ps–ns timescale. The results are consistent with rapid (<1 ps) charge-transfer from NiO to the excited dye (1) to give exclusively the charge-separated state on the timescale of our measurements. Conversely, the TRIR experiments revealed that multiple species are present shortly after excitation of the bodipy chromophore in 2, which is electronically decoupled from the thiophene linker. In solution, excitation first populates the bodipy singlet excited state, followed by charge transfer from the triphenylamine to the bodipy. The presence and short lifetime (τ ≈ 30 ps) of the charge-transfer excited state when 2 is adsorbed on NiO (2|NiO) suggests that charge separation is slower and/or less efficient in 2|NiO than in 1|NiO. This is consistent with the difference in performance between the two dyes in dye-sensitized solar cells and photoelectrochemical water splitting devices. Compared to n-type materials such as TiO2, less is understood regarding electron transfer between dyes and p-type metal oxides such as NiO, but it is evident that fast charge-recombination presents a limit to the performance of photocathodes. This is also a major challenge to photocatalytic systems based on a “Z-scheme”, where the catalysis takes place on a µs–s timescale