Global climate disruption and regional climate shelters after the Toba supereruption.

The Toba eruption ∼74,000 y ago was the largest volcanic eruption since the start of the Pleistocene and represents an important test case for understanding the effects of large explosive eruptions on climate and ecosystems. However, the magnitude and repercussions of climatic changes driven by the eruption are strongly debated. High-resolution paleoclimate and archaeological records from Africa find little evidence for the disruption of climate or human activity in the wake of the eruption in contrast with a controversial link with a bottleneck in human evolution and climate model simulations predicting strong volcanic cooling for up to a decade after a Toba-scale eruption. Here, we use a large ensemble of high-resolution Community Earth System Model (CESM1.3) simulations to reconcile climate model predictions with paleoclimate records, accounting for uncertainties in the magnitude of Toba sulfur emissions with high and low emission scenarios. We find a near-zero probability of annual mean surface temperature anomalies exceeding 4 °C in most of Africa in contrast with near 100% probabilities of cooling this severe in Asia and North America for the high sulfur emission case. The likelihood of strong decreases in precipitation is low in most of Africa. Therefore, even Toba sulfur release at the upper range of plausible estimates remains consistent with the muted response in Africa indicated by paleoclimate proxies. Our results provide a probabilistic view of the uneven patterns of volcanic climate disruption during a crucial interval in human evolution, with implications for understanding the range of environmental impacts from past and future supereruptions.

Ozone impact from solar energetic particles cools the polar stratosphere.

Understanding atmospheric impacts of solar energetic particle precipitation (EPP) remains challenging, from quantification of the response in ozone, to implications on temperature. Both are necessary to understand links between EPP and regional climate variability. Here we use a chemistry-climate model to assess the importance of EPP on late winter/spring polar stratosphere. In transient simulations, the impact on NOy, ozone, and temperature is underestimated when using EPP forcing from the current recommendation of the Coupled Model Intercomparison Project (CMIP6). The resulting temperature response is largely masked by overall dynamical variability. An idealised experiment with EPP forcing that reproduces observed levels of NOy results in a significant reduction of ozone (up to 25%), cooling the stratosphere (up to 3 K) during late winter/spring. Our results unravel the inconsistency regarding the temperature response to EPP-driven springtime ozone decrease, and highlight the need for an improved EPP forcing in climate simulations.

Termination of Solar Cycles and Correlated Tropospheric Variability.

The Sun provides the energy required to sustain life on Earth and drive our planet's atmospheric circulation. However, establishing a solid physical connection between solar and tropospheric variability has posed a considerable challenge. The canon of solar variability is derived from the 400 years of observations that demonstrates the waxing and waning number of sunspots over an 11(-ish) year period. Recent research has demonstrated the significance of the underlying 22 years magnetic polarity cycle in establishing the shorter sunspot cycle. Integral to the manifestation of the latter is the spatiotemporal overlapping and migration of oppositely polarized magnetic bands. We demonstrate the impact of "terminators"-the end of Hale magnetic cycles-on the Sun's radiative output and particulate shielding of our atmosphere through the rapid global reconfiguration of solar magnetism. Using direct observation and proxies of solar activity going back some six decades we can, with high statistical significance, demonstrate a correlation between the occurrence of terminators and the largest swings of Earth's oceanic indices: the transition from El Niño to La Niña states of the central Pacific. This empirical relationship is a potential source of increased predictive skill for the understanding of El Niño climate variations, a high-stakes societal imperative given that El Niño impacts lives, property, and economic activity around the globe. A forecast of the Sun's global behavior places the next solar cycle termination in mid-2020; should a major oceanic swing follow, then the challenge becomes: when does correlation become causation and how does the process work?

Ischaemia-reperfusion modulates inflammation and fibrosis of skeletal muscle after contusion injury.

Regeneration of skeletal muscle following injury is dependent on numerous factors including age, the inflammatory response, revascularization, gene expression of myogenic and growth factors and the activation and proliferation of endogenous progenitor cells. It is our hypothesis that oxidative stress preceding a contusion injury to muscle modulates the inflammatory response to inhibit muscle regeneration and enhance fibrotic scar formation. Male F344/BN rats were assigned to one of four groups. Group 1: uinjured control; Group 2: ischaemic occlusion of femoral vessels for 2 h followed by reperfusion (I-R); Group 3: contusion injury of the tibialis anterior (TA); Group 4: I-R, then contusion injury. The acute inflammatory response (8 h, 3 days) was determined by expression of the chemokine CINC-1, TGF-beta1, IFN-gamma and markers of neutrophil (myeloperoxidase) and macrophage (CD68) activity and recruitment. Acute oxidative stress caused by I-R and/or contusion, was determined by measuring GP91(phox) and lipid peroxidation. Muscle recovery (21 days) was assessed by examining the fibrosis after I-R and contusion injuries to the TA with Sirius Red staining and quantification of collagen I expression. Consistent with our hypothesis, I-R preceding contusion increased all markers of the acute inflammatory response and oxidative stress after injury and elevated the expression of collagen. We conclude that ischaemia-induced oxidative stress exacerbated the inflammatory response and enhanced fibrotic scar tissue formation after injury. This response may be attributable to increased levels of TGF-beta1 and diminished expression of IFN-gamma in the ischaemic contused muscle.

Role of polysialylated neural cell adhesion molecule in rapid eye movement sleep regulation in rats.

Recent evidence suggests that synaptic plasticity occurs during homeostatic processes, including sleep-wakefulness regulation, although the underlying mechanisms are not well understood. Polysialylated neural cell adhesion molecule (PSA NCAM) is a transmembrane protein that has been implicated in various forms of plasticity. To investigate whether PSA NCAM is involved in the neuronal plasticity associated with spontaneous sleep-wakefulness regulation and sleep homeostasis, four studies were conducted using rats. First, we showed that PSA NCAM immunoreactivity is present in close proximity to key neurons in several nuclei of the sleep-wakefulness system, including the tuberomammillary hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. Second, using western blot analysis and densitometric image analysis of immunoreactivity, we found that 6 h of sleep deprivation changed neither the levels nor the general location of PSA NCAM in the sleep-wakefulness system. Finally, we injected endoneuraminidase (Endo N) intracerebroventricularly to examine the effects of polysialic acid removal on sleep-wakefulness states and electroencephalogram (EEG) slow waves at both baseline and during recovery from 6 h of sleep deprivation. Endo N-treated rats showed a small but significant decrease in baseline rapid eye movement (REM) sleep selectively in the late light phase, and a facilitated REM sleep rebound after sleep deprivation, as compared with saline-injected controls. Non-REM sleep and wakefulness were unaffected by Endo N. These results suggest that PSA NCAM is not particularly involved in the regulation of wakefulness or non-REM sleep, but plays a role in the diurnal pattern of REM sleep as well as in some aspects of REM sleep homeostasis.

Autonomic dysreflexia after spinal cord injury: central mechanisms and strategies for prevention.

Spinal reflexes dominate cardiovascular control after spinal cord injury (SCI). These reflexes are no longer restrained by descending control and they can be impacted by degenerative and plastic changes within the injured cord. Autonomic dysreflexia is a condition of episodic hypertension that stems from spinal reflexes initiated by sensory input entering the spinal cord caudal to the site of injury. This hypertension greatly detracts from the quality of life for people with cord injury and can be life-threatening. Changes in the spinal cord contribute substantially to the development of this condition. Rodent models are ideal for investigating these changes. Within the spinal cord, injury-induced plasticity leads to nerve growth factor (NGF)-dependent enlargement of the central arbor of a sub-population of sensory neurons. This enlarged arbor can provide increased afferent input to the spinal reflex, intensifying autonomic dysreflexia. Treatments such as antibodies against NGF can limit this afferent sprouting, and diminish the magnitude of dysreflexia. To assess treatments, a compression model of SCI that leads to progressive secondary damage, and also to some white matter sparing, is very useful. The types of spinal reflexes that likely mediate autonomic dysreflexia are highly susceptible to inhibitory influences of bulbospinal pathways traversing the white matter. Compression models of cord injury reveal that treatments that spare white matter axons also markedly reduce autonomic dysreflexia. One such treatment is an antibody to the integrin CD11d expressed by inflammatory leukocytes that enter the cord acutely after injury and cause significant secondary damage. This antibody blocks integrin-mediated leukocyte entry, resulting in greatly reduced white-matter damage and decreased autonomic dysreflexia after cord injury. Understanding the mechanisms for autonomic dysreflexia will provide us with strategies for treatments that, if given early after cord injury, can prevent this serious disorder from developing.

Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function.

The early inflammatory response to spinal cord injury (SCI) causes significant secondary damage. Strategies that nonselectively suppress inflammation have not improved outcomes after SCI, perhaps because inflammation has both adverse and beneficial effects after SCI. We have shown that the selective, time-limited action of a monoclonal antibody (mAb) to the CD11d subunit of the CD11d/CD18 integrin, delivered intravenously during the first 48 hr after SCI in rats, markedly decreases the infiltration of neutrophils and delays the entry of hematogenous monocyte-macrophages into the injured cord. We hypothesized that this targeted strategy would lead to neuroprotection and improved neurological outcomes. In this study the development of chronic pain was detected in rats by assessing mechanical allodynia on the trunk and hindpaws 2 weeks to 3 months after a clinically relevant clip-compression SCI at the twelfth thoracic segment. The anti-CD11d mAb treatment reduced this pain by half. Motor performance also improved as rats were able to plantar-place their hindpaws and use them for weight support instead of sweeping movements only. Improved cardiovascular outcome was shown after SCI at the fourth thoracic segment by significant decreases in autonomic dysreflexia. Locomotor performance was also improved. These functional changes correlated with significantly greater amounts and increased organization of myelin and neurofilament near the lesion. The improved neurological recovery after the specific reduction of early inflammation after SCI demonstrates that this selective strategy increases tissue at the injury site and improves its functional capacity. This early neuroprotective treatment would be an ideal foundation for building later cell-based therapies.

Methylprednisolone causes minimal improvement after spinal cord injury in rats, contrasting with benefits of an anti-integrin treatment.

Spinal cord injury (SCI) leads to complex secondary events that expand and exacerbate the injury. Methylprednisolone (MP) has been considered a standard of care for acute SCI. The purpose of this study was to test the effects of MP, in severe and more moderate severe clip-compression models of SCI, on the measures of neurological function and lesion sparing that we used previously to assess a highly effective anti-inflammatory therapy, a monoclonal antibody (mAb) to the CD11d integrin. Intravenous treatment with the anti-CD11d mAb blocks the infiltration of leukocytes into the lesion, limits secondary cord damage, and improves neurological outcomes. We also undertook a 2- week study of effects of these two therapies in combination. To permit direct comparison, the new findings with MP are presented together with reference to the previously published effects of the mAb. The severe SCI was at the 4(th) thoracic segment (T4), causing extensive motor dysfunction; the more moderate SCI was at T12 and caused less locomotor loss but the induction of mechanical allodynia. Neither MP alone nor the combination treatment improved Basso, Beattie, and Bresnahan 21-point open-field locomotor scores at 2-12 weeks after SCI. These scores were ~4 points in the control, MP, and combination treatment groups, respectively, at 2 weeks after severe SCI at T4. By 6 weeks after T4 SCI, scores in the control and MP groups were ~7. At 12 weeks after the more moderate T12 injury, scores were ~8 in both control and MP treatment groups. MP treatment had no consistent effect on mechanical allodynia during 12 weeks after SCI. Control and MP-treated rats responded to approximately five of 10 stimuli to their backs and three of 10 stimuli to their hind paws. MP treatment increased areas of neurofilament and myelin near the injury site at T4 and T12. Thus, MP treatment spared tissue, but had no corresponding effect on neurological function. In contrast, the combination treatment did not spare myelin significantly. These neurological outcomes after treatment with MP contrast with the consistent and significant improvements after treatment with the anti-CD11d mAb. Effects of MP on the lesion were significant, but myelin sparing was less than that caused by the anti-CD11d mAb. The presence of MP in the combination therapy appeared to reverse the positive effects of the mAb. The poor neurological outcome after MP treatment may relate to the long-lasting reduction in hematogenous monocyte/macrophages within the injury site that it causes and to the prolongation of a neutrophil presence. These findings demonstrate that the non-selective and enduring effects of immunosuppressive therapy with MP not only fail to improve neurological outcomes, but also can block the beneficial actions of selective therapies such as the anti-CD11d mAb. Combination treatments that cause intense immunosuppression should be viewed with caution.

Autonomic dysreflexia, induced by noxious or innocuous stimulation, does not depend on changes in dorsal horn substance p.

After experimental spinal cord injury (SCI) in rats, autonomic dysreflexia is commonly induced by slightly noxious cutaneous or visceral stimuli. The presence of autonomic dysreflexia is associated with an increase in the afferent fiber arbor area labeled by cholera toxin B or with an anti-CGRP antibody. Our goal was to examine further the sensory afferent input contributing to exaggerated autonomic spinal reflexes and subsequent increases in blood pressure after SCI, typical of autonomic dysreflexia. We observed that changes in blood pressure and heart rate induced by slightly noxious stimuli (2.0-mL balloon colon distension, cutaneous pinch) were increased in magnitude with time after SCI. In contrast, cardiovascular responses induced by non-noxious stimuli (1.0-mL balloon colon distension, light stroking of hair) were relatively constant. We examined substance P-immunoreactive afferent fibers to identify type C, unmyelinated afferent fibers, and A delta lightly myelinated fibers in superficial and deeper laminae of the dorsal horn, respectively. The area of substance P-immunoreactive fibers was quantified in laminae I-V of the dorsal horn. Analysis revealed no difference in substance P afferent fiber area in laminae I-II, or laminae III-V, between sham-injured and SCI rats. These data suggest that noxious, or innocuous, stimulation induces autonomic dysreflexia without expansion of the central arbors of substance P-immunoreactive sensory neurons. Furthermore, autonomic dysreflexia induced by noxious stimulation increases with time after spinal cord injury.

Neutralizing intraspinal nerve growth factor with a trkA-IgG fusion protein blocks the development of autonomic dysreflexia in a clip-compression model of spinal cord injury.

Increased intraspinal nerve growth factor (NGF) after spinal cord injury (SCI) is detrimental to the autonomic nervous system. Autonomic dysreflexia is a debilitating condition characterized by episodic hypertension, intense headache, and sweating. Experimentally, it is associated with aberrant primary afferent sprouting in the dorsal horn that is nerve growth factor (NGF)-dependent. Therapeutic strategies that neutralize NGF may ameliorate initial apoptotic cellular responses to the injury and aberrant afferent plasticity that occurs weeks after the injury. Subsequently, the development of autonomic disorders may be suppressed. We constructed a protein including the extracellular portion of trkA fused to the Fc portion of human IgG and expressed it using a baculovirus system. Binding of our trkA-IgG fusion protein was specific for NGF with a K(d) = 4.26 x 10(-11) M and blocked NGF-dependent neuritogenesis in PC-12 cells. We hypothesized that binding of NGF in the injured cord by our trkA-IgG fusion protein would diminish autonomic dysreflexia. Severe, high thoracic SCI was induced with clip compression and the rats were treated with intrathecal infusions (4 microg/day) of trkA-IgG or control IgG. At 14 days post-SCI, the magnitude of autonomic dysreflexia was assessed. Colon distension increased mean arterial pressure (MAP) in control rats by 46 +/- 2 from 96 +/- 5 mmHg. In contrast, MAP of rats treated with trkA-IgG increased by only 30 +/- 2 mmHg. Likewise, the MAP response to cutaneous stimulation was also reduced in rats treated with trkA-IgG (20 +/- 1 vs. 29 +/- 2). In contrast, trkA-IgG treatment had no effect on heart rate responses during colon distension or cutaneous stimulation. These results indicate that treatment with trkA-IgG to block NGF suppresses the development of autonomic dysreflexia after a clinically relevant spinal cord injury.

Aging-associated oxidative stress modulates the acute inflammatory response in skeletal muscle after contusion injury.

Inflammation is an integral component of the response of skeletal muscle to a contusion injury that can be modulated by acute oxidative stress. Less is known regarding the effect of aging-associated oxidative stress on the inflammatory response in injured skeletal muscle. The purpose of this project was to assess the level of oxidative stress in skeletal muscles of young, adult, and old rats and determine its effect on the acute inflammatory response to a contusion injury. Inherent oxidative stress in the muscle was determined by measuring the glutathione:glutathione disulfide ratio, and levels of GP91(phox). Elevated oxidative stress was observed in uninjured muscles of adult and old rats and was accompanied by increased levels of lipid peroxidation and neutrophil chemoattractant CINC-1. After injury, the acute inflammatory response (8h, 3 d) was determined from markers of neutrophil (myeloperoxidase) and macrophage (CD68) content and by expression of NFkappaB, CINC-1 and TGF-beta1. Compared to injured muscles of young rats, NFkappaB, myeloperoxidase activity (8h), macrophage content (3 d), and TGF-beta1 (8h and 3 d) were significantly greater in injured muscles of old rats. We conclude that aging-associated oxidative stress in muscles of old rats exacerbated the inflammatory response to contusion injury and leads to increased TGF-beta1-induced collagen content.

Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury.

Abstract In this study we explore if loss of GABAergic inhibitory interneurons in the superficial dorsal horn of the spinal cord contributes to reduced GABAergic tone and neuropathic pain following spinal cord injury (SCI). A moderate contusion injury to T11 resulted in the development of mechanical hyperalgesia and thermal hyperalgesia below the level of the lesion in gad1:GFP mice that were alleviated by IP administration of the GABA transporter antagonist tiagabine. Six weeks following SCI a decreased number of GFP(+) neurons were observed in the dorsal horn of SCI animals relative to sham mice. Tissue from a mouse 2 weeks post-SCI was subsequently observed to express activated caspase-3, indicative of apoptosis, co-localized to some GFP(+) GABAergic neurons. Glutamate decarboxylase (GAD)65 and GAD67 immunohistochemical staining was reduced in the dorsal horn of SCI animals. This observation was confirmed in Western blots showing reduced immunoreactivity for GAD67, as well as GABA transporter (GAT)1. Reversal of post-SCI neuropathic pain by tiagabine suggests that reduced GABAergic tone may contribute to hyperalgesia symptoms. This is supported by the subsequent observation that SCI reduced the number of GFP(+) inhibitory neurons, and the finding that some GABAergic GFP(+) neurons undergo cell death at a time point consistent with the development of neuropathic pain following SCI. Concordantly, reductions in both GAD65 and GAD67 and GAT1 immunoreactivity also support the observation of a loss of GABAergic inhibition and the associated spinal interneurons.

Development of autonomic dysreflexia after spinal cord injury is associated with a lack of serotonergic axons in the intermediolateral cell column.

Autonomic dysreflexia consistently develops in patients and in rats after severe upper thoracic spinal cord injury (SCI) as a result of exaggerated spinal sympathetic excitation. In this study we induced episodic hypertension in rats after varying degrees of SCI severity to investigate the contribution of serotonergic bulbospinal axons to the development of autonomic dysreflexia after SCI. Female Wistar rats (250-300 g) were used in all experiments in the following groups: (1) uninjured, (2) clip compression at T4 of 20, 35, or 50 g, (3) spinal cord transection at T4, and (4) intrathecal 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT). Immunohistochemistry for choline acetyl transferase and serotonin (5-HT) was performed on T8-T12 spinal segments to identify sympathetic preganglionic neurons, and to assess 5-HT-containing axons in the intermediolateral cell column (IMLC), respectively. Testing for autonomic dysreflexia was conducted by measuring mean arterial pressure (MAP) at rest and after colon distension-induced hypertension. We observed that the magnitude of the pressor response seen after colon distension correlated with SCI severity and density of 5-HT-immunoreactive axons in the IMLC. Intrathecal administration of the 5-HT(2A) agonist dimethoxy-4-iodamphetamine increased resting MAP and blocked colon distension-induced hypertension, whereas the 5-HT(2A) antagonist ketanserin decreased resting MAP and was permissive to the colon distension-induced pressor response in SCI rats. These results suggest that the SCI-induced loss of serotonergic inputs into the spinal cord IMLC is proportional to the pathogenesis of autonomic dysreflexia and hypotension seen after SCI. We thus conclude that sparing of serotonergic axons beyond a critical threshold preserves cardiovascular regulation and prevents the development of autonomic dysreflexia.

Comparison of effects of methylprednisolone and anti-CD11d antibody treatments on autonomic dysreflexia after spinal cord injury.

Autonomic dysreflexia is a condition of episodic hypertension that develops after spinal cord injury (SCI). We previously showed that a two-day anti-inflammatory treatment with an anti-CD11d integrin monoclonal antibody (mAb), soon after SCI in rats, reduced the magnitude of dysreflexia for at least 6 weeks. Effects of methylprednisolone (MP), a commonly used neuroprotective treatment for SCI, on dysreflexia have never been examined. We compared the effects of a 2-day MP treatment and/or the anti-CD11d mAb on autonomic dysreflexia, elicited by colon distension, after clip-compression SCI at the 4th thoracic segment (T4) in rats. We assessed the effects of each treatment on the size of the calcitonin gene-related peptide (CGRP)-immunoreactive afferent arbour in the dorsal horn, as changes in this arbour can correlate with the development of dysreflexia. MP reduced autonomic dysreflexia by approximately 50% at 2 weeks after SCI, but this effect was lost by 6 weeks. At 2 weeks, the combined effects of MP and the mAb were not additive, reducing dysreflexia by approximately 50%. Neither MP nor the mAb treatment altered the area of CGRP-immunoreactive fibres in the lumbar cord, the crucial input region for dysreflexia initiated by colon distension. However, both treatments led to increased fibre areas in the T9 segment, correlated with greater tissue integrity and smaller lesions, delineated by inflammatory cells. In summary, MP only temporarily decreases autonomic dysreflexia after SCI. The early beneficial effects of both treatments on dysreflexia do not relate to changes in the CGRP-immunoreactive afferent arbour but may correlate with decreased lesion progression.

The N-methyl-D-aspartate receptor splice variant NR1-4 C-terminal domain. Deletion analysis and role in subcellular distribution.

The intracellular C-terminal domain of the N-methyl-d-aspartate receptor (NMDAR) subunits 1 (NR1) and 2 (NR2) are important, if not essential, to the process of NMDAR clustering and anchoring at the plasma membrane and the synapse. Eight NR1 splice variants exist, four of which arise from alternative splicing of the C-terminal exon cassettes. Alternative splice variants may display a differential ability to interact with synaptic anchoring proteins, and splicing of C-terminal exon cassettes may alter the mechanism(s) of subcellular localization and targeting. The NR1-4 isoform has a significantly different C-terminal composition than the prototypic NR1-1 isoform. Whereas the NR1-1 C terminus is composed of C0, C1, and C2 exon cassettes, the NR1-4 C terminus is composed of the C0 and C2' cassettes. In the present study, we address the importance of the NR1-4 C-terminal exon cassettes (C0C2') in subcellular localization in differentiated pheochromocytoma (PC12) cells, in organotypic cultures of dorsal root ganglia, and also in heterologous cells. NR1-4-green fluorescent protein chimeras were created with deletion of either C0, C2', or both cassettes to address their importance in subcellular distribution and cell surface expression of the NR1-4 subunit. These experiments demonstrate that the NR1-4 splice variant found predominantly in the spinal cord uses the C0 cassette, to a large degree, to organize the subcellular distribution of this receptor subunit. Although the role of the C2' subunit is less clear, it may be involved in subunit clustering. However, this clustering is not always as efficient as that attributed to C0 alone or to the natural combination of C0C2'. Finally, although an intact C-terminal domain is neither necessary for interaction with the NR2A subunit nor surface expression of the NR1-4 subunit, the C-terminal domain fragment alone blocks surface expression of native NR1-4, in a dominant negative fashion, when the two are coexpressed.