Reproductive performance of resident and migrant males, females and pairs in a partially migratory bird

We thank everyone from the Centre for Ecology & Hydrology (CEH) who contributed to data collection, and Scottish Natural Heritage for access to the Isle of May National Nature Reserve. We thank the Scottish Ornithologists’ Club (SOC) for their support, and all volunteer observers, particularly Raymond Duncan, Moray Souter and Bob Swann. HG was funded by a Natural Environment Research Council (NERC) CASE studentship supported by CEH and SOC, FD, SW, MPH, MN and SB were funded by NERC and the Joint Nature Conservation Committee, and JMR was part-funded by the Royal Society. Finally, we thank the Associate Editor and two reviewers for constructive comments on the manuscript. The data are available from the Dryad Digital Repository https://doi.org/10.5061/dryad.532j0 (Grist et al., 2017)Peer reviewedPublisher PD

Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment.

Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b+ Ly6G+ neutrophils into the spinal cord. Targeting neutrophils resulted in a reduction in demyelination arguing for a role for these cells in myelin damage. Collectively, these findings emphasize that CXCL1-mediated attraction of neutrophils into the CNS augments demyelination suggesting that this signaling pathway may offer new targets for therapeutic intervention

Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input

AbstractPeripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis.

CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicle-treated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS).IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases

Neuron-immune mechanisms contribute to pain in early stages of arthritis

Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model. Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis andcyto(chemo)kine levels in the early phase of CIA. Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1β levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1β increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs. Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1β in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients

Dynamic and Static Magnetic Resonance Angiography of the Supra-aortic Vessels at 3.0 T Intraindividual Comparison of Gadobutrol, Gadobenate Dimeglumine, and Gadoterate Meglumine at Equimolar Dose

Purpose: The purpose of this study was the intraindividual comparison of a 1.0 M and two 0.5 M gadolinium-based contrast agents (GBCA) using equimolar dosing in dynamic and static magnetic resonance angiography (MRA) of the supra-aortic vessels. Materials and Methods: In this institutional review board-approved study, a total of 20 healthy volunteers (mean +/- SD age, 29 +/- 6 years) underwent 3 consecutive supra-aortic MRA examinations on a 3.0 T magnetic resonance system. The order of GBCA (Gadobutrol, Gadobenate dimeglumine, and Gadoterate meglumine) was randomized with a minimum interval of 48 hours between the examinations. Before each examination and 45 minutes after each examination, circulatory parameters were recorded. Total GBCA dose per MRA examination was 0.1 mmol/kg with a 0.03 mmol/kg and 0.07 mmol/kg split for dynamic and static MRA, respectively, injected at a rate of 2 mL/s. Two blinded readers qualitatively assessed static MRA data sets independently using pairwise rankings (superior, inferior, and equal). In addition, quantitative analysis was performed with signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) evaluation as well as vessel sharpness analysis of static MRA using an in-house-developed semiautomated tool. Dynamic MRA was evaluated for maximal SNR. Statistical analysis was performed using the Cohen kappa, the Wilcoxon rank sum tests, and mixed effects models. Results: No significant differences of hemodynamic parameters were observed. In static MRA, Gadobutrol was rated superior to Gadoterate meglumine (P 0.05). Maximal SNR in dynamic MRA using Gadobutrol was significantly higher than both comparators at the level of the proximal and distal internal carotid artery (P < 0.05 and P < 0.05; P < 0.05 and P < 0.05). Conclusions: At equimolar doses, 1.0 M Gadobutrol demonstrates higher SNR/CNR than do Gadobenate dimeglumine and Gadoterate meglumine, with superior image quality as compared with Gadoterate meglumine for dynamic and static carotid MRA. Despite the shortened bolus with Gadobutrol, no blurring of vessel edges was observed

Impact of Social Buffering and Restraint on Welfare Indicators during UK Commercial Horse Slaughter

Simple Summary Retrospective CCTV footage was analysed by trained observers to assess the welfare of horses co-slaughtered with a conspecific present or slaughtered individually, restrained or unrestrained. Co-slaughtered horses were found to move around the kill pen more but were less likely to slip/fall in the pen. Both individually slaughtered horses and loose (unrestrained) horses were more likely to show agitated behaviour and resist entry to the pen, with unrestrained horses also showing increased agonistic behaviour towards abattoir personnel. Horses showed affiliative behaviour towards each other when co-slaughtered, with the shooting of the first horse seldom eliciting a startled response from the second horse. This study shows that enabling abattoirs to co-slaughter unrestrained horses could minimise stress and maximise both human safety and horse welfare. The results of this study are relevant on a wider scale, with countries across the world slaughtering high numbers of unhandled or semi-feral horses, and encourage further research to guide welfare improvements in this area. Current legislation in the United Kingdom stipulates that horses should not be slaughtered within sight of one another. However, abattoir personnel anecdotally report that, for semi-feral horses unused to restraint, co-slaughtering alongside a conspecific could reduce distress through social buffering and improve safety, but there is a lack of evidence to support this. CCTV footage from an English abattoir was assessed retrospectively with welfare indicators from when horses entered the kill pen until they were killed. Of 256 horses analysed, 12% (32/256) were co-slaughtered (alongside a conspecific) and 88% (224/256) individually. Co-slaughtered horses moved more in the pen, but individually slaughtered horses showed more agitated behaviour, required more encouragement to enter the kill pen, and experienced more slips or falls. Unrestrained horses (40%; 102/256) showed increased agitation, movement, and agonistic behaviour towards the operator and resisted entry to the kill pen compared to restrained horses (60%; 154/256). Positive interactions between conspecifics were seen in 94% (30/32) of co-slaughtered horses, and only 6% (1/16) showed a startled response to the first horse being shot, with a median time of 15 s between shots. This study highlights the impact that both conspecific and human interactions can have on equine welfare at slaughter. Semi-feral or unrestrained horses appear to experience increased distress compared to horses more familiar with human handling, and the presence of a conspecific at slaughter mitigated this

Tracing oceanic sources of heat content available for Atlantic hurricanes

In the Main Development Region (MDR) for Atlantic hurricanes, the volume of water warmer than 26.5°C quantifies the potential source of energy for major storms. Taking a Lagrangian perspective, this warm water is backtracked on seasonal timescales in an eddy-resolving ocean model hindcast spanning 1988–2010. Being confined near the surface and assuming a mixed layer depth of 50 m, net heat fluxes into or out of water parcels advected toward the MDR are inferred from along-trajectory temperature tendencies. To first order, these heat fluxes match surface net heat fluxes during the months over which water advects into the region. Contributions to this warm water in the preceding 6 months include water resident in the MDR (20%–40%), arriving via the North Brazil Current (NBC, 5%–15%), or via Ekman drift across 10°S. In relative terms, decreased contributions from the NBC and Ekman drift and more in situ warming within the MDR lead to warmer, more active hurricane seasons

Hyperpolarized carbon 13 MRI: clinical applications and future directions in oncology

Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology