Effects of a Hazing-Light System on Migration and Collision Avoidance of Eiders at an Artificial Oil-Production Island, Arctic Alaska

During migration, Common and King Eiders (Somateria mollissima and S. spectabilis) cross the Beaufort and Chukchi Seas of Arctic Alaska. Because they may become attracted to lights, eiders are susceptible to collision with structures, including offshore oil facilities. We used ornithological radar in 2001 – 04 to characterize the behavior of eiders migrating past Northstar Island, an oil-production island near Prudhoe Bay, Alaska, and to assess the effects of a hazing-light system on migrating eiders. “Eider” radar targets exhibited pulsed, irregular periods of movement; movement rates were higher when sea ice was present, without precipitation, and during tailwinds and crosswinds but were not affected by lights. Velocities (ground speeds) were higher when ice was present and with strong tailwinds. They were lower at night when the lights were on, but higher during the day when the lights were on. Radar targets exhibited little variation in flight behavior as they passed the island; the proportion of non-directional behavior was larger when ice was present, with tailwinds, with weak winds, and near the full moon when it was not visible. Lights had no effect on flight behavior. Birds tended to exhibit more course changes as they approached the island, greater angular changes when they changed course, and larger net increases in passing distance as a result of those course changes when the lights were on; however, none of these differences were statistically significant. Overall, the hazing lights at Northstar did not disrupt the birds’ migratory movements but resulted in increased avoidance of the island.En période de migration, l’eider à duvet et l’eider à tête grise (Somateria mollissima et S. spectabilis) survolent la mer de Beaufort et la mer des Tchouktches dans l’Alaska de l’Arctique. Comme ils sont attirés par les lumières, les eiders risquent d’entrer en collision avec des structures, y compris les installations pétrolières au large. De 2001 à 2004, nous avons utilisé un radar ornithologique pour caractériser le comportement des eiders qui migrent au-delà de l’île Northstar, une île de production pétrolière près de Prudhoe Bay, en Alaska, et pour évaluer les effets d’un système d’éclairage de dispersion sur les eiders en migration. Les « eiders » ciblés par le radar présentaient des périodes de mouvement pulsées et irrégulières; les taux de mouvement étaient plus importants en présence de glace marine, en l’absence de précipitation et en présence de vent arrière et de vent latéral, mais n’étaient pas touchés par les lumières. Les vélocités (vitesses au sol) étaient plus élevées en présence de glace et de forts vents arrière. Elles étaient plus basses la nuit lorsque les lumières étaient allumées, mais plus élevées le jour lorsque les lumières étaient allumées. Nous avons observé peu de variation quant au comportement de vol des cibles atteintes par le radar pendant qu’elles survolaient l’île; la proportion de comportements de vol non directionnels était plus importante en présence de glace, de vent arrière, de vent faible et lorsque la pleine lune n’était pas visible. Les lumières n’ont pas eu d’impact sur le comportement de vol. Lorsque les lumières étaient allumées, les oiseaux avaient tendance à changer de direction plus souvent durant leur vol à l’approche de l’île et à effectuer de plus grandes variations angulaires lorsqu’ils changeaient de direction, puis présentaient une nette augmentation de la distance de passage à la suite de ces changements de direction. Toutefois, aucune de ces différences n’était statistiquement importante. En général, les lumières de dispersion de l’île Northstar n’ont pas nui aux mouvements migratoires des oiseaux, mais ces derniers ont davantage évité de voler près de l’île

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density

Gravin Orchestrates Protein Kinase A and β2-Adrenergic Receptor Signaling Critical for Synaptic Plasticity and Memory

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage

De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge

Automated quantification of retinal vessel morphometry in the UK Biobank Cohort

The following topics are dealt with: feature extraction; learning (artificial intelligence); image classification; image segmentation; computer vision; object detection; feedforward neural nets; image colour analysis; image representation; medical image processing

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria

Suitability of UK biobank retinal images for automatic analysis of morphometric properties of the vasculature

To assess the suitability of retinal images held in the UK Biobank--the largest retinal data repository in a prospective population-based cohort--for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease.Non-mydriatic fundus images from both eyes of 2,690 participants--people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345)--were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry.Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001).A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe