Synthesis of [11C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography.

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4-5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

Qualitative analysis of the barriers and facilitators influencing uptake of direct-acting antiviral therapy for hepatitis C in a primary healthcare environment.

Historical interferon and ribavirin therapies for hepatitis C virus have been replaced by modern treatments with improved efficacy and tolerability. Despite the availability of direct-acting antiviral therapy, evidence demonstrates poor uptake in Australia. Presently, the barriers and facilitators influencing uptake of direct-acting antiviral therapy are not fully understood, especially in a primary healthcare environment. Our study aimed to discover methods of improving uptake of treatment in the community. We conducted 15 semi-structured, face-to-face interviews in a metropolitan, primary healthcare clinic in Australia. Interviews were recorded, transcribed and subsequently analysed using thematic content analysis. We identified patient-related and healthcare system-related barriers and facilitators to commencing treatment. This included established themes from current literature, and novel themes unique to direct-acting antiviral therapy and primary care. Overall, our study reinforces the importance of public health campaigns to promote community awareness and emphasises the concomitant role of mental health in fostering treatment uptake. Informed by our findings, we suggest further research on an integrated model of care, focused on the domains of disease awareness, patient engagement and treatment adherence. Hence, a community-oriented approach, driven by primary healthcare, ultimately underpins a successful public strategy to improve outcomes for patients affected by hepatitis C.

Reduced mRNA secondary-structure stability near the start codon indicates functional genes in prokaryotes.

Several recent studies have found that selection acts on synonymous mutations at the beginning of genes to reduce mRNA secondary-structure stability, presumably to aid in translation initiation. This observation suggests that a metric of relative mRNA secondary-structure stability, Z(ΔG), could be used to test whether putative genes are likely to be functionally important. Using the Escherichia coli genome, we compared the mean Z(ΔG) of genes with known functions, genes with known orthologs, genes where function and orthology are unknown, and pseudogenes. Genes in the first two categories demonstrated similar levels of selection for reduced stability (increased Z(ΔG)), whereas for pseudogenes stability did not differ from our null expectation. Surprisingly, genes where function and orthology were unknown were also not different from the null expectation, suggesting that many of these open reading frames are not functionally important. We extended our analysis by constructing a Bayesian phylogenetic mixed model based on data from 145 prokaryotic genomes. As in E. coli, genes with no known function had consistently lower Z(ΔG), even though we expect that many of the currently unannotated genes will ultimately have their functional utility discovered. Our findings suggest that functional genes tend to evolve increased Z(ΔG), whereas nonfunctional ones do not. Therefore, Z(ΔG) may be a useful metric for identifying genes of potentially important function and could be used to target genes for further functional study.

Increasing the imaging depth of coherent anti-Stokes Raman scattering microscopy with a miniature microscope objective.

A miniature objective lens with a tip diameter of 1.3 mm was used for extending the penetration depth of coherent anti-Stokes Raman scattering (CARS) microscopy. Its axial and lateral focal widths were determined to be 11.4 and 0.86 microm, respectively, by two-photon excitation fluorescence imaging of 200 nm beads at a 735 nm excitation wavelength. By inserting the lens tip into a soft gel sample, CARS images of 2 microm polystyrene beads 5 mm deep from the surface were acquired. The miniature objective was applied to CARS imaging of rat spinal cord white matter with a minimal requirement for surgery.