Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition

Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD

Oculomotor involvement in spatial working memory is task-specific

Many everyday tasks, such as remembering where you parked, require the capacity to store and manipulate information about the visual and spatial properties of the world. The ability to represent, remember, and manipulate spatial information is known as visuospatial working memory (VSWM). Despite substantial interest in VSWM the mechanisms responsible for this ability remain debated. One influential idea is that VSWM depends on activity in the eye-movement (oculomotor) system. However, this has proved difficult to test because experimental paradigms that disrupt oculomotor control also interfere with other cognitive systems, such as spatial attention. Here, we present data from a novel paradigm that selectively disrupts activation in the oculomotor system. We show that the inability to make eye-movements is associated with impaired performance on the Corsi Blocks task, but not on Arrow Span, Visual Patterns, Size Estimation or Digit Span tasks. It is argued that the oculomotor system is required to encode and maintain spatial locations indicted by a change in physical salience, but not non-salient spatial locations indicated by the meaning of a symbolic cue. This suggestion offers a way to reconcile the currently conflicting evidence regarding the role of the oculomotor system in spatial working memory

Discrete classification and electron energy spectra of Titan's varied magnetospheric environment

We analyse combined electron spectra across the dynamic range of both Cassini electron sensors in order to characterise the background plasma environment near Titan for 54 Cassini-Titan encounters as of May 2009. We characterise the encounters into four broad types: Plasma sheet, Lobe-like, Magnetosheath and Bimodal. Despite many encounters occurring close to the magnetopause only two encounters to date were predominantly in the magnetosheath (T32 and T42). Bimodal encounters contain two distinct electron populations, the low energy component of the bi-modal populations is apparently associated with local water group products. Additionally, a hot lobe-like environment is also occasionally observed and is suggestively linked to increased local pick-up. We find that 34 of 54 encounters analysed are associated with one of these groups while the remaining encounters exhibit a combination of these environments. We provide typical electron properties and spectra for each plasma regime and list the encounters appropriate to each. Citation: Rymer, A.M., H. T. Smith, A. Wellbrock, A.J. Coates, and D.T. Young (2009), Discrete classification and electron energy spectra of Titan's varied magnetospheric environment, Geophys. Res. Lett., 36, L15109, doi: 10.1029/2009GL039427

Survival and recovery of Phaeocystis antarctica (Prymnesiophyceae) from prolonged darkness and freezing

The colony-forming haptophyte Phaeocystis antarctica is an important primary producer in the Ross Sea, and must survive long periods of darkness and freezing temperature in this extreme environment. We conducted experiments on the responses of P. antarctica-dominated phytoplankton assemblages to prolonged periods of darkness and freezing. Chlorophyll and photosynthetic capacity of the alga declined nonlinearly and independently of each other in the dark, and darkness alone would potentially reduce photosynthetic capacity by only 60 per cent over 150 days (approximately the length of the Antarctic winter in the southern Ross Sea). The estimated reduction of colonial mucous carbon is higher than that of colonial cell carbon, suggesting metabolism of the colonial matrix in the dark. The alga quickly resumed growth upon return to light. Phaeocystis antarctica also survived freezing, although longer freezing durations lengthened the lag before growth resumption. Particulate dimethylsulfoniopropionate relative to chlorophyll increased upon freezing and decreased upon darkness. Taken together, the abilities of P. antarctica to survive freezing and initiate growth quickly after darkness may provide it with the capability to survive in both the ice and the water column, and help explain its repeated dominance in austral spring blooms in the Ross Sea and elsewhere in the Southern Ocean

Comparison of alternative approaches for analysing multi-level RNA-seq data

RNA sequencing (RNA-seq) is widely used for RNA quantification in the environmental, biological and medical sciences. It enables the description of genome-wide patterns of expression and the identification of regulatory interactions and networks. The aim of RNA-seq data analyses is to achieve rigorous quantification of genes/transcripts to allow a reliable prediction of differential expression (DE), despite variation in levels of noise and inherent biases in sequencing data. This can be especially challenging for datasets in which gene expression differences are subtle, as in the behavioural transcriptomics test dataset from D. melanogaster that we used here. We investigated the power of existing approaches for quality checking mRNA-seq data and explored additional, quantitative quality checks. To accommodate nested, multi-level experimental designs, we incorporated sample layout into our analyses. We employed a subsampling without replacement-based normalization and an identification of DE that accounted for the hierarchy and amplitude of effect sizes within samples, then evaluated the resulting differential expression call in comparison to existing approaches. In a final step to test for broader applicability, we applied our approaches to a published set of H. sapiens mRNA-seq samples, The dataset-tailored methods improved sample comparability and delivered a robust prediction of subtle gene expression changes. The proposed approaches have the potential to improve key steps in the analysis of RNA-seq data by incorporating the structure and characteristics of biological experiments

Theoretical investigation of measuring cerebral blood flow in the adult human head using bolus Indocyanine Green injection and near-infrared spectroscopy

To investigate the accuracy of measuring cerebral blood flow (CBF) using a bolus injection of Indocyanine Green (ICG) detected by near-infrared spectroscopy in adult human heads, simulations were performed using a two-layered model representing the extracerebral and intracerebral layers. Modeled optical data were converted into tissue ICG concentration using either the one-detector modified Beer-Lambert law (MBLL) method, or the two-detector partial path-length (PPL) method. The CBFs were estimated using deconvolution and blood flow index techniques. Using the MBLL method, the CBFs were significantly underestimated but the PPL method improved their accuracy and robustness, especially when used as relative measures. The dispersion of the arterial input function also affected the CBF estimates. (c) 2007 Optical Society of America

Anomalous microwave emission from spinning nanodiamonds around stars

Several interstellar environments produce 'anomalous microwave emission' (AME), with brightness peaks at tens-of-gigahertz frequencies. The emission's origins are uncertain -- rapidly spinning nanoparticles could emit electric-dipole radiation, but the polycyclic aromatic hydrocarbons that have been proposed as the carrier are now found not to correlate with Galactic AME signals. The difficulty is in identifying co-spatial sources over long lines of sight. Here we identify AME in three proto-planetary discs. These are the only known systems that host hydrogenated nanodiamonds, in contrast to the very common detection of polycyclic aromatic hydrocarbons. Using spectroscopy, the nanodiamonds are located close to the host stars, at physically well-constrained temperatures. Developing disc models, we reproduce the emission with diamonds 0.75--1.1 nm in radius, holding <= 1-2% of the carbon budget. Ratios of microwave emission to stellar luminosity are approximately constant, allowing nanodiamonds to be ubiquitous but emitting below detection thresholds in many star systems. This result is compatible with the findings with similar-sized diamonds found within Solar System meteorites. As nanodiamond spectral absorption is seen in interstellar sightlines, these particles are also a candidate for generating galaxy-scale AME

Predictive validity of A-level grades and teacher-predicted grades in UK medical school applicants: a retrospective analysis of administrative data in a time of COVID-19

OBJECTIVES: To compare in UK medical students the predictive validity of attained A-level grades and teacher-predicted A levels for undergraduate and postgraduate outcomes. Teacher-predicted A-level grades are a plausible proxy for the teacher-estimated grades that replaced UK examinations in 2020 as a result of the COVID-19 pandemic. The study also models the likely future consequences for UK medical schools of replacing public A-level examination grades with teacher-predicted grades. DESIGN: Longitudinal observational study using UK Medical Education Database data. SETTING: UK medical education and training. PARTICIPANTS: Dataset 1: 81 202 medical school applicants in 2010–2018 with predicted and attained A-level grades. Dataset 2: 22 150 18-year-old medical school applicants in 2010–2014 with predicted and attained A-level grades, of whom 12 600 had medical school assessment outcomes and 1340 had postgraduate outcomes available. OUTCOME MEASURES: Undergraduate and postgraduate medical examination results in relation to attained and teacher-predicted A-level results. RESULTS: Dataset 1: teacher-predicted grades were accurate for 48.8% of A levels, overpredicted in 44.7% of cases and underpredicted in 6.5% of cases. Dataset 2: undergraduate and postgraduate outcomes correlated significantly better with attained than with teacher-predicted A-level grades. Modelling suggests that using teacher-estimated grades instead of attained grades will mean that 2020 entrants are more likely to underattain compared with previous years, 13% more gaining the equivalent of the lowest performance decile and 16% fewer reaching the equivalent of the current top decile, with knock-on effects for postgraduate training. CONCLUSIONS: The replacement of attained A-level examination grades with teacher-estimated grades as a result of the COVID-19 pandemic may result in 2020 medical school entrants having somewhat lower academic performance compared with previous years. Medical schools may need to consider additional teaching for entrants who are struggling or who might need extra support for missed aspects of A-level teaching

Preliminary interpretation of Titan plasma interaction as observed by the Cassini Plasma Spectrometer: Comparisons with Voyager 1

The Cassini Plasma Spectrometer (CAPS) instrument observed the plasma environment at Titan during the Cassini orbiter's TA encounter on October 26, 2004. Titan was in Saturn's magnetosphere during the Voyager 1 flyby and also during the TA encounter. CAPS measurements from this encounter are compared with measurements made by the Voyager 1 Plasma Science Instrument (PLS). The comparisons focus on the composition and nature of ambient and pickup ions. They lead to: A) the major ion components of Saturn's magnetosphere in the vicinity of Titan are H+, H-2(+) and O+/CH4+ ions; B) finite gyroradius effects are apparent in ambient O+ ions as the result of their absorption by Titan's extended atmosphere; C) the principal pickup ions are composed of H+, H-2(+), N+/CH2+, CH4+, and N-2(+); D) the pickup ions are in narrow energy ranges; and E) there is clear evidence of the slowing down of background ions due to pickup ion mass loading