Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice

Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6nclf), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration

Tissue-Specific Requirement for the GINS Complex During Zebrafish Development

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages

Tissue-Specific Requirement for the GINS Complex During Zebrafish Development.

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages

High star formation rates as the origin of turbulence in early and modern disk galaxies

High spatial and spectral resolution observations of star formation and kinematics in early galaxies have shown that two-thirds are massive rotating disk galaxies with the remainder being less massive non-rotating objects. The line of sight averaged velocity dispersions are typically five times higher than in today's disk galaxies. This has suggested that gravitationally-unstable, gas-rich disks in the early Universe are fuelled by cold, dense accreting gas flowing along cosmic filaments and penetrating hot galactic gas halos. However these accreting flows have not been observed, and cosmic accretion cannot power the observed level of turbulence. Here we report on a new sample of rare high-velocity-dispersion disk galaxies we have discovered in the nearby Universe where cold accretion is unlikely to drive their high star-formation rates. We find that the velocity dispersion is most fundamentally correlated with their star-formation rates, and not their mass nor gas fraction, which leads to a new picture where star formation itself is the energetic driver of galaxy disk turbulence at all cosmic epochs.Comment: 9 pages, 2 figures, Supplimentary Info available at: http://pulsar.swin.edu.au/~agreen/nature/sigma_mean_arXiv.pdf. Accepted for publication in Natur

Pre-surgical depression and anxiety and recovery following coronary artery bypass graft surgery

We aimed to explore the combined contribution of pre-surgical depression and anxiety symptoms for recovery following coronary artery bypass graft (CABG) using data from 251 participants. Participants were assessed prior to surgery for depression and anxiety symptoms and followed up at 12 months to assess pain and physical symptoms, while hospital emergency admissions and death/major adverse cardiac events (MACE) were monitored on average 2.68 years after CABG. After controlling for covariates, baseline anxiety symptoms, but not depression, were associated with greater pain (β = 0.231, p = 0.014) and greater physical symptoms (β = 0.194, p = 0.034) 12 months after surgery. On the other hand, after controlling for covariates, baseline depression symptoms, but not anxiety, were associated with greater odds of having an emergency admission (OR 1.088, CI 1.010–1.171, p = 0.027) and greater hazard of death/MACE (HR 1.137, CI 1.042–1.240, p = 0.004). These findings point to different pathways linking mood symptoms with recovery after CABG surgery

A feasibility study exploring the role of pre-operative assessment when examining the mechanism of ‘chemo-brain’ in breast cancer patients

Background: Women receiving chemotherapy treatment for breast cancer may experience problems with their memory and attention (cognition), which is distressing and interferes with quality of life. It is unclear what causes or contributes to the problems they report: psychological distress, fatigue, coping style, or specific biological changes for example to pro inflammatory cytokines. Research shows however, that approximately a third of women with breast cancer perform poorly on tests of cognition before commencing chemotherapy. We aimed to examine the acceptability and relevance of pre-surgical assessments (bloods, brain imaging, cognitive tests and self-report questionnaires) when investigating the phenomenon of ‘chemo-brain’ and investigate whether inflammatory markers mediate chemotherapy-induced neuropsychological impairments in women treated for breast cancer. Methods: Women with early stage breast cancer completed neuropsychological and quality of life assessments at T1 (pre-surgery), T2 (post-surgery before chemotherapy) and T3 (6 months later). Blood cytokine levels were measured at the same time points and brain imaging was performed at T1 and T3. Results: In total, 14/58 women participated (8 chemotherapy, 6 non-chemotherapy). Prior to the start of chemotherapy a decline in cognitive performance compared to baseline was observed in one participant. At T3 women who received chemotherapy reported poorer quality of life and greater fatigue. Increases in soluble tumour necrosis factor receptor II (sTNFRII), interleukin-6, interleukin-10 and vascular endothelial growth factor occurred post chemotherapy only. Levels of sTNFRII were inversely correlated with grey matter volume (GMV) of the right posterior insula in both groups. At T3, the chemotherapy group displayed a greater reduction in GMV in the subgenual and dorsal anterior cingulate, and the inferior temporal gyrus. Conclusions: Pre-operative recruitment to the study was challenging; however, the lack of significant changes in blood cytokine levels and neuropsychological tests at T2 implies that post surgery may be a valid baseline assessment, but this needs further investigation in a larger study. The preliminary results support the hypothesis that chemotherapy induced fatigue is mediated by a change in peripheral cytokine levels which could explain some symptoms of ‘chemo brain’ experienced by patients

Management and prevention of chronic obstructive pulmonary disease exacerbations: a state of the art review

Exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this prevalent and devastating condition. This review provides a concise, state of the art summary on prevention and management of exacerbations. Considerable new data underpins evidence in support of many preventative interventions, pharmacological and non-pharmacological, that are now available. Challenges remain in developing new approaches, and delivering those that already exist to the right patient at the right time. Management of an exacerbation remains stepwise according to clinical severity, but there is now additional focus on addressing comorbidities and taking the opportunity at acute events to optimise preventative strategies for the future. Ultimately, exacerbations are heterogeneous events in a heterogeneous disease, and an individualised approach is paramount