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Working memory (WM) enables the temporary storage of limited information and is a central component of higher order cognitive function. Irrelevant and/or distracting information can have a negative impact on WM processing and suppressing such incoming stimuli is critical to maintaining adequate performance. However, the neural mechanisms and dynamics underlying such distractor inhibition remain poorly understood. In the current study, we enrolled 46 healthy adults (Mage: 27.92, Nfemale: 28) who completed a Sternberg type WM task with high- and low-distractor conditions during magnetoencephalography (MEG). MEG data were transformed into the time-frequency domain and significant task-related oscillatory responses were imaged to identify the underlying anatomical areas. Whole-brain paired t-tests, with cluster-based permutation testing for multiple comparisons correction, were performed to assess differences between the low- and high-distractor conditions for each oscillatory response. Across conditions, we found strong alpha and beta oscillations (i.e., decreases relative to baseline) and increases in theta power throughout the encoding and maintenance periods. Whole-brain contrasts revealed significantly stronger alpha and beta oscillations in bilateral prefrontal regions during maintenance in high- compared to low-distractor trials, with the stronger beta oscillations being centered on the left dorsolateral prefrontal cortex and right inferior frontal gyrus, while those for alpha being within the right anterior prefrontal cortices and the right middle frontal gyrus. These findings suggest that alpha and beta oscillations in the bilateral prefrontal cortices play a major role in the inhibition of distracting information during WM maintenance. Our results also contribute to prior research on cognitive control and functional inhibition, in which prefrontal regions have been widely implicated.

Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29–76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4–8 Hz), alpha (10–16 Hz), and gamma (74–98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.

Tidal turbines are one source of marine renewable energy but development of tidal power is hampered by uncertainties in fish-turbine interaction impacts. Current knowledge gaps exist in efforts to quantify risks, as empirical data and modeling studies have characterized components of fish approach and interaction with turbines, but a comprehensive model that quantifies conditional occurrence probabilities of fish approaching and then interacting with a turbine in sequential steps is lacking. We combined empirical acoustic density measurements of Pacific herring (Clupea pallasii) and when data limited, published probabilities in an impact probability model that includes approach, entrainment, interactions, and avoidance of fish with axial or cross-flow tidal turbines. Interaction impacts include fish collisions with stationary turbine components, blade strikes by rotating blades, and/or a collision followed by a blade strike. Impact probabilities for collision followed by a blade strike were lowest with estimates ranging from 0.0000242 to 0.0678, and highest for blade strike ranging from 0.000261 to 0.40. Maximum probabilities occurred for a cross-flow turbine at night with no active or passive avoidance. Estimates were lowest when probabilities were conditional on sequential events, and when active and passive avoidance was included for an axial-flow turbine during the day. As expected, conditional probabilities were typically lower than analogous independent events and literature values. Estimating impact probabilities for Pacific herring in Admiralty Inlet, Washington, United States for two device types illustrates utilization of existing data and simultaneously identifies data gaps needed to fully calculate empirical-based probabilities for any site-species combination.

Cerebellar ataxia is the poorly coordinated movement that results from injury or disease affecting the cerebellum. The diagnosis and assessment of ataxia are significantly challenging due to dependency on clinicians’ experience and the attendant subjectivity of such a process. In recent years, neuroimaging and sensor-based approaches, supported by effective machine learning techniques have made advances in the pursuit of addressing these clinical challenges. In this work, we present an outline of approaches to applying machine learning to this clinical challenge. We first provide a fundamental clinical overview with practical problems and then from a machine learning perspective, outline possible approaches with which to address these clinical challenges. Also discussed are the limitations in existing methods, the provision of cross disciplinary approaches and the current state-of-the-art as a potential basis for future research.

We present 1.8 yr of near-daily Swift monitoring of the bright, strongly variable Type 1 active galactic nucleus (AGN) Fairall 9. Totaling 575 successful visits, this is the largest such campaign reported to date. Variations within the UV/optical are well correlated, with longer wavelengths lagging shorter wavelengths in the direction predicted by thin-disk/lamppost models. The correlations are improved by “detrending,” subtracting a second-order polynomial fit to the UV/optical light curves to remove long-term trends that are not of interest to this study. Extensive testing indicates detrending with higher-order polynomials removes too much intrinsic variability signal on reverberation timescales. These data provide the clearest detection to date of interband lags within the UV, indicating that neither emission from a large disk nor diffuse continuum emission from the broad-line region (BLR) can independently explain the full observed lag spectrum. The observed X-ray flux variations are poorly correlated with those in the UV/optical. Further, subdivision of the data into four ∼160 days light curves shows that the UV/optical lag spectrum is highly stable throughout the four periods, but the X-ray to UV lags are unstable, significantly changing magnitude and even direction from one period to the next. This indicates the X-ray to UV relationship is more complex than predicted by the simple reprocessing model often adopted for AGN. A “bowl” model (lamppost irradiation and blackbody reprocessing on a disk with a steep rim) fit suggests the disk thickens at a distance (∼10 lt-day) and temperature (∼8000 K) consistent with the inner edge of the BLR.

Abstract Background Cerebellar ataxia refers to the disturbance in movement resulting from cerebellar dysfunction. It manifests as inaccurate movements with delayed onset and overshoot, especially when movements are repetitive or rhythmic. Identification of ataxia is integral to the diagnosis and assessment of severity, and is important in monitoring progression and improvement. Ataxia is identified and assessed by clinicians observing subjects perform standardised movement tasks that emphasise ataxic movements. Our aim in this paper was to use data recorded from motion sensors worn while subjects performed these tasks, in order to make an objective assessment of ataxia that accurately modelled the clinical assessment. Methods Inertial measurement units and a Kinect© system were used to record motion data while control and ataxic subjects performed four instrumented version of upper extremities tests, i.e. finger chase test (FCT), finger tapping test (FTT), finger to nose test (FNT) and dysdiadochokinesia test (DDKT). Kinematic features were extracted from this data and correlated with clinical ratings of severity of ataxia using the Scale for the Assessment and Rating of Ataxia (SARA). These features were refined using Feed Backward feature Elimination (the best performing method of four). Using several different learning models, including Linear Discrimination, Quadratic Discrimination Analysis, Support Vector Machine and K-Nearest Neighbour these extracted features were used to accurately discriminate between ataxics and control subjects. Leave-One-Out cross validation estimated the generalised performance of the diagnostic model as well as the severity predicting regression model. Results The selected model accurately ( $$96.4\%$$ 96.4 % ) predicted the clinical scores for ataxia and correlated well with clinical scores of the severity of ataxia ( $$rho = 0.8$$ r h o = 0.8 , $$p < 0.001$$ p < 0.001 ). The severity estimation was also considered in a 4-level scale to provide a rating that is familiar to the current clinically-used rating of upper limb impairments. The combination of FCT and FTT performed as well as all four test combined in predicting the presence and severity of ataxia. Conclusion Individual bedside tests can be emulated using features derived from sensors worn while bedside tests of cerebellar ataxia were being performed. Each test emphasises different aspects of stability, timing, accuracy and rhythmicity of movements. Using the current models it is possible to model the clinician in identifying ataxia and assessing severity but also to identify those test which provide the optimum set of data. Trial registration Human Research and Ethics Committee, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia (HREC Reference Number: 11/994H/16).

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell–intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.

IntroductionCholesterol levels have been associated with age-related cognitive decline, however, such an association has not been comprehensively explored in people with Parkinson’s disease (PD). To address this uncertainty, the current cross-sectional study examined the cholesterol profile and cognitive performance in a cohort of PD patients.MethodsCognitive function was evaluated using two validated assessments (ACE-R and SCOPA-COG) in 182 people with PD from the Australian Parkinson’s Disease Registry. Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and Triglyceride (TRG) levels were examined within this cohort. The influence of individual lipid subfractions on domain-specific cognitive performance was investigated using covariate-adjusted generalised linear models.ResultsFemales with PD exhibited significantly higher lipid subfraction levels (TC, HDL, and LDL) when compared to male counterparts. While accounting for covariates, HDL levels were strongly associated with poorer performance across multiple cognitive domains in females but not males. Conversely, TC and LDL levels were not associated with cognitive status in people with PD.ConclusionHigher serum HDL associates with poorer cognitive function in females with PD and presents a sex-specific biomarker for cognitive impairment in PD.

Predation mortality can influence the distribution and abundance of fish populations. While predation is often assessed using direct observations of prey consumption, potential predation can be predicted from co-occurring predator and prey densities under varying environmental conditions. Juvenile Pacific salmon Oncorhynchus spp. (i.e., smolts) from the Columbia River Basin experience elevated mortality during the transition from estuarine to ocean habitat, but a thorough understanding of the role of predation remains incomplete. We used a Holling type II functional response to estimate smolt predation risk based on observations of piscivorous seabirds (sooty shearwater [Ardenna griseus] and common murre [Uria aalge]) and local densities of alternative prey fish including northern anchovy (Engraulis mordax) in Oregon and Washington coastal waters during May and June 2010-2012. We evaluated predation risk relative to the availability of alternative prey and physical factors including turbidity and Columbia River plume area, and compared risk to returns of adult salmon. Seabirds and smolts consistently co-occurred at sampling stations throughout most of the study area (mean = 0.79 ± 0.41, SD), indicating that juvenile salmon are regularly exposed to avian predators during early marine residence. Predation risk for juvenile coho (Oncorhynchus kisutch), yearling Chinook salmon (O. tshawytscha), and subyearling Chinook salmon was on average 70% lower when alternative prey were present. Predation risk was greater in turbid waters, and decreased as water clarity increased. Juvenile coho and yearling Chinook salmon predation risk was lower when river plume surface areas were greater than 15,000 km2, while the opposite was estimated for subyearling Chinook salmon. These results suggest that plume area, turbidity, and forage fish abundance near the mouth of the Columbia River, all of which are influenced by river discharge, are useful indicators of potential juvenile salmon mortality that could inform salmonid management.

Although Arctic marine ecosystems are changing rapidly, year-round monitoring is currently very limited and presents multiple challenges unique to this region. The Chukchi Ecosystem Observatory (CEO) described here uses new sensor technologies to meet needs for continuous, high-resolution, and year-round observations across all levels of the ecosystem in the biologically productive and seasonally ice-covered Chukchi Sea off the northwest coast of Alaska. This mooring array records a broad suite of variables that facilitate observations, yielding better understanding of physical, chemical, and biological couplings, phenologies, and the overall state of this Arctic shelf marine ecosystem. While cold temperatures and 8 months of sea ice cover present challenging conditions for the operation of the CEO, this extreme environment also serves as a rigorous test bed for innovative ecosystem monitoring strategies. Here, we present data from the 2015–2016 CEO deployments that provide new perspectives on the seasonal evolution of sea ice, water column structure, and physical properties, annual cycles in nitrate, dissolved oxygen, phytoplankton blooms, and export, zooplankton abundance and vertical migration, the occurrence of Arctic cod, and vocalizations of marine mammals such as bearded seals. These integrated ecosystem observations are being combined with ship-based observations and modeling to produce a time series that documents biological community responses to changing seasonal sea ice and water temperatures while establishing a scientific basis for ecosystem management.

Whether or not neurogenesis occurs in the adult substantia nigra pars compacta (SNc) is an important question relevant for developing better treatments for the motor symptoms of Parkinson's disease (PD). Although controversial, it is generally believed that dividing cells here remain undifferentiated or differentiate into glia, not neurons. However, there is a suggestion that Nestin-expressing neural precursor cells (NPCs) in the adult SNc have a propensity to differentiate into neurons, which we sought to confirm in the present study. Adult (>8-weeks old) transgenic NesCreERT2/GtROSA or NesCreERT2/R26eYFP mice were used to permanently label Nestin-expressing cells and their progeny with β-galactosidase (β-gal) or enhanced yellow fluorescent protein (eYFP), respectively. Most β-gal+ or eYFP+ cells were found in the ependymal lining of the midbrain aqueduct (Aq) and in the midline ventral to Aq. Smaller but significant numbers were in the periaqueductal gray (PAG), the ventral tegmental area (VTA), and in SNc. Low-level basal proliferation was evidenced by a modest increase in number of β-gal+ or eYFP+ cells over time, fewer β-gal+ or eYFP+ cells when mice were administered the anti-mitotic agent Cytarabine, and incorporation of the proliferation marker bromodeoxyuridine (BrdU) in a very small number of β-gal+ cells. No evidence of migration was found, including no immunoreactivity against the migration markers doublecortin (DCX) or polysialic acid neural cell adhesion molecule (PSA-NCAM), and no dispersal of β-gal+ or eYFP+ cells through the midbrain parenchyma over time. However, β-gal+ or eYFP+ cells did increase in size and express higher levels of mature neuronal genes over time, indicating growth and neuronal differentiation. In mice whose SNc dopamine neurons had been depleted with 6-hydroxy-dopamine, a model of PD, there were ~2-fold more β-gal+ cells in SNc specifically, although the proportion that were also NeuN+ was not affected. Remarkably, as early as 4 days following putative Nestin-expression, many β-gal+ or eYFP+ cells had mature neuronal morphology and were NeuN+. Furthermore, mature neuronal β-gal+ cells were immunoreactive against the self-renewal or pluripotency marker sex determining region Y-box 2 (Sox2). Overall, our data support the notion that some Nestin-expressing, presumably NPCs, have a limited capacity for proliferation, no capacity for migration, and a propensity to generate new neurons within the microenvironment of the adult midbrain. However, our data also suggest that significant numbers of extant midbrain neurons express Nestin and other classical neurogenesis markers in contexts that are presumably not neurogenic. These findings foreshadow duplicitous roles for Nestin and other molecules that are traditionally associated with neurogenesis in the adult midbrain, which should be considered in future PD research.

Background. Heightened impulsivity has been reported in a subset of people with Parkinson’s disease (PwP) and is considered a risk factor for the development of impulse control disorders (ICDs). However, at present, there are no recognised biochemical markers of heightened impulsivity. Objectives. To determine if ceruloplasmin, a serum marker involved in the regulation of iron and copper homeostasis, is associated with trait impulsivity in PwP. Methods. The study measured serum ceruloplasmin and impulsivity using the Barratt Impulsiveness Scale (BIS-11) in an Australian cohort of 214 PwP. Multivariate general linear models (GLMs) were used to identify whether higher serum ceruloplasmin levels (>75th percentile) were significantly predictive of BIS-11 scores. Results. Serum ceruloplasmin was higher in females with PD (p

Commercial viability of Marine Renewable Energy (MRE) is progressing but no national or international monitoring standards have been established for wave or tidal energy sites. Standardized monitoring within and across MRE sectors is necessary to expedite project permitting/consenting, detect environmental impacts, and enable comparison among sites and technologies. Acoustic backscatter from a bottom-deployed platform at a pilot wave energy site off Newport, Oregon was compared to data collected at a tidal turbine site in Admiralty Inlet, Washington. Metrics that describe fish and macrozooplankton densities and vertical distributions derived from acoustic backscattered energy were compared using wavelets and Autoregressive Moving Average models (ARMA). Average density and vertical distribution values significantly differed between sites. Metrics of density and location in the water column displayed diel (24 h) and tidal (12 h) cycles. Dispersion of animals in the water column varied at 64- and 128-h periods at both sites. Applicability of methods in both sectors suggests that a standard approach to biological monitoring is possible. Stationary acoustics and analytic methods presented here can be used to characterize pre-installation conditions and refine post-installation monitoring to site-specific characteristics to ensure cost-effective detection of impacts associated with MRE development.

Background. Studies attempting to elucidate an association between homocysteine and symptom progression in Parkinson’s disease (PD) have had largely discrepant findings. This study aimed to investigate elevated serum homocysteine levels and symptom progression in a cohort of PD patients. Methods. Serum homocysteine, folate, and vitamin B12 levels were measured in 205 people with PD and 78 age-matched healthy controls. People with Parkinson’s disease underwent a battery of clinical assessments to evaluate symptom severity, including motor (MDS-UPDRS) and cognitive (ACE-R) assessments. Multivariate generalised linear models were created, controlling for confounding variables, and were used to determine whether serum markers are associated with various symptom outcome measures. Results. People with Parkinson’s disease displayed significantly elevated homocysteine levels (p

The inflammatory response within the central nervous system (CNS) is a tightly regulated cascade of events which is a balance of both cytotoxic and cytotrophic effects which determine the outcome of an injury. The two effects are inextricably linked, particularly in traumatic brain injury or stroke, where permanent dysfunction is often observed. Chronic brain inflammation is a key barrier to regeneration. This is considered a toxic, growth inhibitory mechanism; yet, the inflammatory response must also be considered as a mechanism that can be exploited as protective and reparative. Repurposing this complex response is the challenge for tissue engineers: to design treatments to repair and regenerate damaged tissue after brain insult. Astrocytes are important cells within the CNS which play a key role after traumatic brain injury. A comprehensive understanding of their functions—both cytotrophic and cytotoxic—will enable designed materials and drug delivery approaches for improved treatment options post traumatic injury. Understanding, evaluating, and designing biomaterials that match the healthy neural environment to temporally alter the inflammatory cascade represent a promise neural tissue engineering strategy to optimise repair and regeneration after injury.

Intense, ephemeral foraging events within localized hot spots represent important trophic transfers to top predators in marine ecosystems, though the spatial extent and temporal overlap of predators and prey are difficult to observe using traditional methods. The southeastern Bering Sea has high marine productivity along the shelf break, especially near marine canyons. At a hot spot located near Bering Canyon, we observed three foraging events over a 12 day period in June 2005. These were located by aerial surveys, quantified by airborne lidar and visual counts, and characterized by ship-based acoustics and net catches. Because of the high density of seabirds, the events could be seen in images from space-based synthetic aperture radar. The events developed at the shelf slope, adjacent to passes between the Aleutian Islands, persisted for 1 to 8 days, then abruptly disappeared. Build-up and break down of the events occurred on 24 hr time scales, and diameters ranged from 10 to 20 km. These events comprised large concentrations of euphausiids, copepods, herring, other small pelagic fishes, humpback whales, Dall’s porpoise, short-tailed shearwaters, northern fulmars, and other pelagic seabirds. The lidar and acoustic remote sensing data demonstrated that prey densities inside the events were several times higher than those outside, indicating the importance of including events in forage fish surveys. This implies a need for either very intensive traditional surveys covering large expanses or for adaptive surveys guided by remote sensing. To our knowledge, this is the first time that an Alaskan hot spot was monitored with the combination of airborne and satellite remote sensing.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the authors.The authors became aware of an issue with incorrect loading control images being presented and are now retracting the article in the interests of maintaining their publication standards and those of the journal. The authors maintain that these presentational errors do not impact the underlying scientific findings of the article, some of which have been verified in other laboratories.Figure 4 contains incorrect loading control images of SOD1G93A mouse. The b-actin images blots presented are SOD1G93A rat b-actin bands that were accidentally used when compiling the image for publication. Similarly, in Figure 1 the samples were run in two separate experiments with the controls split across the two blots. The b-actin for one set of controls was accidentally used for the second controls. The authors state that quantifications were performed using the correct b-actin bands.In figure 1, concerns were raised that each of the panels had 13 lanes except for the ATF panel which appeared to have only twelve lanes. The authors state that the ATF6 panel has 13 lanes, but last two control lanes of the gel have no signal, making it difficult to accurately align the end part of the gel correctly for display in the figure.

Recent evidence indicates the number of dopaminergic neurons in the adult rodent hypothalamus and midbrain is regulated by environmental cues, including photoperiod, and that this occurs via up- or down-regulation of expression of genes and proteins that are important for dopamine (DA) synthesis in extant neurons ('DA neurotransmitter switching'). If the same occurs in humans, it may have implications for neurological symptoms associated with DA imbalances. Here we tested whether there are differences in the number of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) and DA transporter (DAT) immunoreactive neurons in the midbrain of people who died in summer (long-day photoperiod, n = 5) versus winter (short-day photoperiod, n = 5). TH and DAT immunoreactivity in neurons and their processes was qualitatively higher in summer compared with winter. The density of TH immunopositive (TH+) neurons was significantly (~6-fold) higher whereas the density of TH immunonegative (TH-) neurons was significantly (~2.5-fold) lower in summer compared with winter. The density of total neurons (TH+ and TH- combined) was not different. The density of DAT+ neurons was ~2-fold higher whereas the density of DAT- neurons was ~2-fold lower in summer compared with winter, although these differences were not statistically significant. In contrast, midbrain nuclear volume, the density of supposed glia (small TH- cells), and the amount of TUNEL staining were the same in summer compared with winter. This study provides the first evidence of an association between environmental stimuli (photoperiod) and the number of midbrain DA neurons in humans, and suggests DA neurotransmitter switching underlies this association.

Effective management and development of new treatment strategies for response fluctuations in advanced Parkinson's disease (PD) largely depends on clinical rating instruments such as the PD home diary. The Parkinson's kinetigraph (PKG) measures movement accelerations and analyzes the spectral power of the low frequencies of the accelerometer data. New algorithms convert each hour of continuous PKG data into one of the three motor categories used in the PD home diary, namely motor Off state and On state with and without dyskinesia.To compare quantitative motor state assessment in fluctuating PD patients using the PKG with motor state ratings from PD home diaries.Observational cohort study on 24 in-patients with documented motor fluctuations who completed diaries by rating motor Off, On without dyskinesia, On with dyskinesia, and asleep for every hour for 5 consecutive days. Simultaneously collected PKG data (recorded between 6 am and 10 pm) were analyzed and calibrated to the patient's individual thresholds for Off and dyskinetic state by novel algorithms classifying the continuous accelerometer data into these motor states for every hour between 6 am and 10 pm.From a total of 2,040 hours, 1,752 hours (87.4%) were available for analyses from calibrated PKG data (7.5% sleeping time and 5.1% unclassified motor state time were excluded from analyses). Distributions of total motor state hours per day measured by PKG showed moderate-to-strong correlation to those assessed by diaries for the different motor states (Pearson's correlations coefficients: 0.404-0.658), but inter-rating method agreements on the single-hour-level were only low-to-moderate (Cohen's κ: 0.215-0.324).The PKG has been shown to capture motor fluctuations in patients with advanced PD. The limited correlation of hour-to-hour diary and PKG recordings should be addressed in further studies.

Astrocytes provide trophic, structural and metabolic support to neurons, and are considered genuine targets in regenerative neurobiology, as their phenotype arbitrates brain integrity during injury. Inhibitors of Rho kinase (ROCK) cause stellation of cultured 2D astrocytes, increased L-glutamate transport, augmented G-actin, and elevated expression of BDNF and anti-oxidant genes. Here we further explored the signposts of a cytotrophic, healthy phenotype by data-mining of our astrocytic transcriptome in the presence of Fasudil. Gene expression profiles of motor and autophagic cellular cascades and inflammatory / angiogenic responses were all inhibited, favouring adoption of an anti-migratory phenotype. Like ROCK inhibition, tissue engineered bioscaffolds can influence the extracellular matrix. We built upon our evidence that astrocytes maintained on 3D poly-Ɛ-caprolactone (PCL) electrospun scaffolds adopt a cytotrophic phenotype similar to that produced by Fasudil. Using these procedures, employing mature 3D cultured astrocytes, Fasudil (100 µM) or Y27632 (30 µM) added for the last 72 h of culture altered arborization, which featured numerous additional minor processes as shown by GFAP and AHNAK immunolabelling. Both ROCK inhibitors decreased F-actin, but increased G-actin labelling, indicative of disassembly of actin stress fibres. ROCK inhibitors provide additional beneficial effects for bioengineered 3D astrocytes, including enlargement of the overall arbour. Potentially, the combined strategy of bio-compatible scaffolds with ROCK inhibition offers unique advantages for the management of glial scarring. Overall these data emphasize that manipulation of the astrocyte phenotype to achieve a healthy biology offers new hope for the management of inflammation in neuropathologies.

Establishing the presence and severity of fluctuations is important in managing Parkinson's Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system.The Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm.This Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations.The Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges.

Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα-, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females.

Bioenergetic abnormalities and metabolic dysfunction occur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models. However, whether metabolic dysfunction occurs early in ALS pathophysiology linked to different ALS genes remains unclear. Here, we investigated AMP-activated protein kinase (AMPK) activation, which is a key enzyme induced by energy depletion and metabolic stress, in neuronal cells and mouse models expressing mutant superoxide dismutase 1 (SOD1) or TAR DNA binding protein 43 (TDP-43) linked to ALS. AMPK phosphorylation was sharply increased in spinal cords of transgenic SOD1G93A mice at disease onset and accumulated in cytoplasmic granules in motor neurons, but not in presymptomatic mice. AMPK phosphorylation also occurred in peripheral tissues, liver and kidney, in SOD1G93A mice at disease onset, demonstrating that AMPK activation occurs late and is not restricted to motor neurons. Conversely, AMPK activity was drastically diminished in spinal cords and brains of presymptomatic and symptomatic transgenic TDP-43A315T mice and motor neuronal cells expressing different TDP-43 mutants. We show that mutant TDP-43 induction of the AMPK phosphatase, protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models. Furthermore, PP2A inhibition by okadaic acid reversed AMPK inactivation by mutant TDP-43 in neuronal cells. Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice. While AMPK activation in motor neurons correlates with progression in mutant SOD1-mediated disease, AMPK inactivation mediated by PP2A is associated with mutant TDP-43-linked ALS.

In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.

Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1.

Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/γ-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons.

During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a-/- mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.

Attempts to repair the central nervous system damaged as a result of trauma or disease will depend on the ability to restore the appropriate neuronal connectivity. This will rely on establishing appropriate chemical and physical environments for supporting neural cells and their processes and in this regard, engineering of biomaterials is of increasing interest. It will be important to understand how cells behave on these biomaterials in vitro, prior to future in vivo application. We reveal that modification of 3-dimensional (3D) electrospun poly-ε-caprolactone (PCL) nanofiber scaffolds by fiber alignment and aminolysation is superior to classical 2-dimensional (2D) culture-ware in promoting in vitro proliferation and differentiation of cortical cells. Many studies have examined the importance of exogenous soluble factors to promote cell fate specification. Here, we demonstrate that tethering the neurotrophin, brain-derived neurotrophic factor (BDNF), onto modified nanofibers is superior to culturing in the presence of soluble BDNF. Functional immobilization of BDNF to polymer nanofibers enhances neural stem cell (NSC) proliferation and directs cell fate toward neuronal and oligodendrocyte specification, essential for neural tissue repair. These findings indicate that modified PCL nanofibrous 3D scaffolds are capable of supporting NSCs and their derivatives and may present a new avenue for encouraging neural repair in the future. [ABSTRACT FROM AUTHOR]

Personality Disorder is a serious mental health condition affecting between 5-12% of the UK population (Bolton et al., 2014). The NICE guideline for the treatment and management of borderline personality disorder (NICE, 2009) does not identify occupational therapy as an intervention. However, occupational therapists are routinely working with this population. There is an urgent need for occupational therapists to explain their theoretical models and evidence effective practice with this population. This seminar will explore the evolution of occupational therapy over thirteen years within the Leeds Personality Disorder Managed Clinical Network (LPDMCN). The task has been to construct a credible and relevant form of occupational therapy that engages effectively with the complexity of personality disorder. One challenge has been to keep an occupation-centred approach (Fisher, 2014) while working within psychologically driven frameworks. A further challenge has been to utilise suitable frames of reference that can help explain the multiple functions of service users' occupational lives. The occupational therapy process within LPDMCN is described. Relevant theoretical models are outlined and applied using case examples. Occupation-based and occupation-focused methods, tools and interventions are illustrated. The concept of 'occupational traps' is introduced and explored using clinical examples. It is argued that occupational therapy should be an integral component of the personality disorder care pathway because it: • produces an occupational profile which contributes to the overall case formulation • enhances the therapeutic relationship through 'doing together' • develops and reinforces self-regulation skills • can potentially move the service user beyond the identity of personality disorder. [ABSTRACT FROM AUTHOR]

Planet population synthesis models predict an abundance of planets with semimajor axes between 1 and 10 au, yet they lie at the edge of the detection limits of most planet finding techniques. Discovering these planets and studying their distribution is critical to understanding the physical processes that drive planet formation. ROME/REA is a gravitational microlensing project whose main science driver is to discover exoplanets in the cold outer regions of planetary systems. To achieve this, it uses a novel approach combining a multiband survey with reactive follow-up observations, exploiting the unique capabilities of the Las Cumbres Observatory global network of robotic telescopes combined with a Target and Observation Manager system. We present the main science objectives and a technical overview of the project, including initial results. [ABSTRACT FROM AUTHOR]

Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of ‘wearing off’ and dyskinaesia in Parkinsons disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until ∼60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, l-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by l-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in l-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and ‘wearing off’. [ABSTRACT FROM AUTHOR]