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"Burt, M."
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Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
New vessel formation relies on a tightly controlled switch in endothelial biology from proliferating to specializing phenotypes. Here, Fang et al. elucidate the molecular mechanisms of this switch and show that the arterial shear activates a Notch-Cx37-p27 axis promoting endothelial cell cycle arrest and enabling arterial gene expression.
Journal Article
Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking
Oxycodone abuse frequently begins with prescription oral oxycodone, yet vulnerability factors (e.g. sex, genetics) determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1-, 4-, and 16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p < 0.001). Both sexes increased intake between 4-h and 16-h sessions (p < 2e-16), but a subset of strains augmented intake at 16-h (p = 0.0005). Heritability ( h 2 ) of active licks during 4-h sessions at increasing oxycodone dose ranged from 0.30 to 0.53. Under a progressive ratio (PR) schedule, breakpoints were strain-dependent (p < 2e-16). Cued reinstatement was greater in females (p < 0.001). Naive rats were assessed using elevated plus maze (EPM), open field (OF), and novel object interaction (NOI) tests. We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas OF and NOI traits were more associated with SA in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and anxiety correlates with multiple SA parameters across strains.
Journal Article
Aerial surveys of seabirds: the advent of digital methods
1. Aerial seabird surveys are often conducted so that changes in abundance may be monitored. For example, large-scale offshore wind farms are proposed for UK waters, and surveys are currently being conducted to quantify numbers and distribution ahead of construction. 2. Technological advances mean that strip transect surveys may now be conducted, using digital methods. We address survey design and data analysis issues for such digital surveys, contrasting them with visual aerial line transect surveys. 3. We also explore the relative performances of the methods for estimating the size of a large aggregation of common scoters in Carmarthen Bay, Wales. We found that abundance estimates from two digital methods were closely comparable, while estimates from visual aerial surveys were appreciably lower. 4. Synthesis and applications. Efficient survey methods to quantify abundance and distribution of seabirds are needed, to assess change arising from climate change, or developments such as the construction of large-scale offshore wind farms. The traditional survey methods are visual surveys conducted along transects from ships or aircraft. Digital video and stills surveys can be conducted from aircraft flying sufficiently high to avoid disturbance, while still being able to detect and identify seabirds. Given the rapid technological developments, we expect digital surveys largely to replace visual surveys for seabirds in offshore regions.
Journal Article
Sudden collapse of a mesopredator reveals its complementary role in mediating rocky reef regime shifts
While changes in the abundance of keystone predators can have cascading effects resulting in regime shifts, the role of mesopredators in these processes remains underexplored. We conducted annual surveys of rocky reef communities that varied in the recovery of a keystone predator (sea otter, Enhydra lutris) and the mass mortality of a mesopredator (sunflower sea star, Pycnopodia helianthoides) due to an infectious wasting disease. By fitting a population model to empirical data, we show that sea otters had the greatest impact on the mortality of large sea urchins, but that Pycnopodia decline corresponded to a 311% increase in medium urchins and a 30% decline in kelp densities. Our results reveal that predator complementarity in size-selective prey consumption strengthens top-down control on urchins, affecting the resilience of alternative reef states by reinforcing the resilience of kelp forests and eroding the resilience of urchin barrens. We reveal previously underappreciated species interactions within a ‘classic’ trophic cascade and regime shift, highlighting the critical role of middle-level predators in mediating rocky reef state transitions.
Journal Article
Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models
At the turn of the last century, the emerging field of medical oncology chose a cytotoxic approach to cancer therapy over an immune-centered approach at a time when evidence in support of either paradigm did not yet exist. Today, nearly 120 years of data have established that (a) even the best cytotoxic regimens only infrequently cure late-stage malignancy and (b) strategies that supplement and augment existing antitumor immune responses offer the greatest opportunities to potentiate durable remission in cancer. Despite widespread acceptance of these paradigms today, the ability of the immune system to recognize and fight cancer was a highly controversial topic for much of the twentieth century. Why this modern paradigmatic mainstay should have been both dubious and controversial for such an extended period is a topic of considerable interest that merits candid discussion. Herein, we review the literature to identify and describe the watershed events that ultimately led to the acceptance of immunotherapy as a viable regimen for the treatment of neoplastic malignancy. In addition to noting important clinical discoveries, we also focus on research milestones and the development of critical model systems in rodents and dogs including the advanced modeling techniques that allowed development of patient-derived xenografts. Together, their use will further our understanding of cancer biology and tumor immunology, allow for a speedier assessment of the efficacy and safety of novel approaches, and ultimately provide a faster bench to beside transition.
Journal Article
Inactivation of phosphodiesterase-4B gene in rat nucleus accumbens shell by CRISPR/Cas9 or positive allosteric modulation of the protein affects the motivation to chronically self-administer nicotine
Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we used a reverse translational approach. We inactivated
PDE4B
in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats. These rats then were given 23-h chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the PDE4B
-
edited group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5-dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These reverse translational studies in rats provide insight into the motivational effects of NAcs PDE4B that advance our understanding of the smoking behaviors mapped in human GWAS.
Journal Article
Adaptive capacity
Because of the complexity and speed of environmental, climatic, and socio-political change in coastal marine social-ecological systems, there is significant academic and applied interest in assessing and fostering the adaptive capacity of coastal communities. Adaptive capacity refers to the latent ability of a system to respond proactively and positively to stressors or opportunities. A variety of qualitative, quantitative, and participatory approaches have been developed and applied to understand and assess adaptive capacity, each with different benefits, drawbacks, insights, and implications. Drawing on case studies of coastal communities from around the globe, we describe and compare 11 approaches that are often used to study adaptive capacity of social and ecological systems in the face of social, environmental, and climatic change. We synthesize lessons from a series of case studies to present important considerations to frame research and to choose an assessment approach, key challenges to analyze adaptive capacity in linked social-ecological systems, and good practices to link results to action to foster adaptive capacity. We suggest that more attention be given to integrated social-ecological assessments and that greater effort be placed on evaluation and monitoring of adaptive capacity over time and across scales. Overall, although sustainability science holds a promise of providing solutions to real world problems, we found that too few assessments seem to lead to tangible outcomes or actions to foster adaptive capacity in social-ecological systems.
Journal Article
Time-resolved relaxation and fragmentation of polycyclic aromatic hydrocarbons investigated in the ultrafast XUV-IR regime
Polycyclic aromatic hydrocarbons (PAHs) play an important role in interstellar chemistry and are subject to high energy photons that can induce excitation, ionization, and fragmentation. Previous studies have demonstrated electronic relaxation of parent PAH monocations over 10–100 femtoseconds as a result of beyond-Born-Oppenheimer coupling between the electronic and nuclear dynamics. Here, we investigate three PAH molecules: fluorene, phenanthrene, and pyrene, using ultrafast XUV and IR laser pulses. Simultaneous measurements of the ion yields, ion momenta, and electron momenta as a function of laser pulse delay allow a detailed insight into the various molecular processes. We report relaxation times for the electronically excited PAH
*
, PAH
+*
and PAH
2+*
states, and show the time-dependent conversion between fragmentation pathways. Additionally, using recoil-frame covariance analysis between ion images, we demonstrate that the dissociation of the PAH
2+
ions favors reaction pathways involving two-body breakup and/or loss of neutral fragments totaling an even number of carbon atoms.
Polycyclic aromatic hydrocarbons play an important role in interstellar chemistry, where interaction with high energy photons can induce ionization and fragmentation reactions. Here the authors, with XUV-IR pump-probe experiments, investigate the ultrafast photoinduced dynamics of fluorene, phenanthrene and pyrene, providing insight into their preferred reaction channels.
Journal Article