Sea-anemone toxin ATX-II elicits A-fiber-dependent pain and enhances resurgent and persistent sodium currents in large sensory neurons

Background

Despite decades of intense research efforts, actions of acute opioids are not fully understood. Increasing evidence suggests that in addition to well-documented antinociceptive effects opioids also produce paradoxical hyperalgesic and excitatory effects on neurons. However, most studies focus on the pronociceptive actions of chronic opioid exposure. Matrix metalloproteinase 9 (MMP-9) plays an important role in neuroinflammation and neuropathic pain development. We examined MMP-9 expression and localization in dorsal root ganglia (DRGs) after acute morphine treatment and, furthermore, the role of MMP-9 in modulating acute morphine-induced analgesia and hyperalgesia in mice.

Results

Subcutaneous morphine induced a marked up-regulation of MMP-9 protein in DRGs but not spinal cords. Morphine also increased MMP-9 activity and mRNA expression in DRGs. MMP-9 up-regulation peaked at 2 h but returned to the baseline after 24 h. In DRG tissue sections, MMP-9 is expressed in small and medium-sized neurons that co-express mu opioid receptors (MOR). In DRG cultures, MOR agonists morphine, DAMGO, and remifentanil each increased MMP-9 expression in neurons, whereas the opioid receptor antagonist naloxone and the MOR-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP) suppressed morphine-induced MMP-9 expression. Notably, subcutaneous morphine-induced analgesia was enhanced and prolonged in Mmp9 knockout mice and also potentiated in wild-type mice receiving intrathecal injection of MMP-9 inhibitors. Consistently, intrathecal injection of specific siRNA targeting MMP-9 reduced MMP-9 expression in DRGs and enhanced and prolonged morphine analgesia. Subcutaneous morphine also produced heat hyperalgesia at 24 h, but this opioid-induced hyperalgesia was not enhanced after MMP-9 deletion or inhibition.

Conclusions

Transient MMP-9 up-regulation in DRG neurons can mask opioid analgesia, without modulating opioid-induced hyperalgesia. Distinct molecular mechanisms (MMP-9 dependent and independent) control acute opioid-induced pronociceptive actions (anti-analgesia in the first several hours and hyperalgesia after 24 h). Targeting MMP-9 may improve acute opioid analgesia.     

Cognitive function in adolescence and the risk for premature diabetes and cardiovascular mortality in adulthood

Background

Epidemiological studies have demonstrated a relationship between cognitive function in youth and the future risk of death. Less is known regarding the relationship with diabetes related death. This study assessed the relationship between cognitive function in late adolescence and the risk for diabetes, cardiovascular- (CVD) and all-cause mortality in adulthood.

Methods

This retrospective study linked data from 2,277,188 16–19 year olds who had general intelligence tests (GIT) conducted during pre-military recruitment assessment with cause of death as coded by the Israel Central Bureau of Statistics. The associations between cognitive function and cause-specific mortality were assessed using Cox models.

Results

There were 31,268 deaths that were recorded during 41,916,603 person-years of follow-up, with a median follow-up of 19.2 (IQR 10.7, 29.5) years. 3068, 1443, 514 and 457 deaths were attributed to CVD, CHD, stroke, and diabetes, respectively. Individuals in the lowest GIT vs. highest GIT quintiles in unadjusted models had the highest risk for all-cause mortality (HR 1.84, 95% CI 1.78, 1.91), total CVD (HR 3.32, 95% CI 2.93, 3.75), CHD (HR 3.49 95% CI 2.92, 4.18), stroke (HR 3.96 95% CI 2.85, 5.5) and diabetes-related (HR 6.96 95% CI 4.68, 10.36) mortality. These HRs were attenuated following adjustment for age, sex, birth year, body-mass index, residential socioeconomic status, education and country of origin for all-cause (HR 1.23, 95% CI 1.17, 1.28), CVD (HR 1.76, 95% CI 1.52, 2.04), CHD (HR 1.7 95% CI 1.37, 2.11), stroke (HR 2.03, 95% CI 1.39, 2.98) and diabetes-related (HR 3.14 95% CI 2.00, 4.94) mortality. Results persisted in a sensitivity analyses limited to participants with unimpaired health at baseline and that accounted competing risk.

Conclusions

This analysis of over 2 million demonstrates a strong relationship between cognitive function at youth and the risk for diabetes, all-cause and CVD-related mortality independent of adolescent obesity.

     

Viral Mediated Redirection of NEMO/IKK�� to Autophagosomes Curtails the Inflammatory Cascade

The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response.     

Feeder use predicts both acquisition and transmission of a contagious pathogen in a North American songbird

Individual heterogeneity can influence the dynamics of infectious diseases in wildlife and humans alike. Thus, recent work has sought to identify behavioural characteristics that contribute disproportionately to individual variation in pathogen acquisition (super-receiving) or transmission (super-spreading). However, it remains unknown whether the same behaviours enhance both acquisition and transmission, a scenario likely to result in explosive epidemics. Here, we examined this possibility in an ecologically relevant host–pathogen system: house finches and their bacterial pathogen, Mycoplasma gallisepticum, which causes severe conjunctivitis. We examined behaviours likely to influence disease acquisition (feeder use, aggression, social network affiliations) in an observational field study, finding that the time an individual spends on bird feeders best predicted the risk of conjunctivitis. To test whether this behaviour also influences the likelihood of transmitting M. gallisepticum, we experimentally inoculated individuals based on feeding behaviour and tracked epidemics within captive flocks. As predicted, transmission was fastest when birds that spent the most time on feeders initiated the epidemic. Our results suggest that the same behaviour underlies both pathogen acquisition and transmission in this system and potentially others. Identifying individuals that exhibit such behaviours is critical for disease management.     

Caribbean massive corals not recovering from repeated thermal stress events during 2005–2013

Massive coral bleaching events associated with high sea surface temperatures are forecast to become more frequent and severe in the future due to climate change. Monitoring colony recovery from bleaching disturbances over multiyear time frames is important for improving predictions of future coral community changes. However, there are currently few multiyear studies describing long‐term outcomes for coral colonies following acute bleaching events. We recorded colony pigmentation and size for bleached and unbleached groups of co‐located conspecifics of three major reef‐building scleractinian corals (Orbicella franksi, Siderastrea siderea, and Stephanocoenia michelini; n = 198 total) in Bocas del Toro, Panama, during the major 2005 bleaching event and then monitored pigmentation status and changes live tissue colony size for 8 years (2005–2013). Corals that were bleached in 2005 demonstrated markedly different response trajectories compared to unbleached colony groups, with extensive live tissue loss for bleached corals of all species following bleaching, with mean live tissue losses per colony 9 months postbleaching of 26.2% (±5.4 SE) for O. franksi, 35.7% (±4.7 SE) for S. michelini, and 11.2% (±3.9 SE) for S. siderea. Two species, O. franksi and S. michelini, later recovered to net positive growth, which continued until a second thermal stress event in 2010. Following this event, all species again lost tissue, with previously unbleached colony species groups experiencing greater declines than conspecific sample groups, which were previously bleached, indicating a possible positive acclimative response. However, despite this beneficial effect for previously bleached corals, all groups experienced substantial net tissue loss between 2005 and 2013, indicating that many important Caribbean reef‐building corals will likely suffer continued tissue loss and may be unable to maintain current benthic coverage when faced with future thermal stress forecast for the region, even with potential benefits from bleaching‐related acclimation.     

Demographic response to shading and defoliation in two woodland orchids

Many woodland herbs are long-lived, clonal geophytes that have evolved life histories favoring survival over reproduction. We examined the life history responses of natural populations of two woodland orchid species,Cypripedium calceolus andCephalanthera longifolia to defoliation and heavy shading conducted early in the growing seasons of 2002 and 2003. We asked whether, in view of the importance of growth for the survival of geophytes, treated plants were more likely to exhibit reduced flowering than reduced vegetative growth in the seasons following treatment. We also asked whether plants would suffer reduced ramet performance. Both treatments led to significant declines in flower number per ramet, number of leaves per ramet, and mean ramet height relative to controls inCypripedium. However, inCephalanthera, only shaded plants exhibited significant declines in flower number per ramet, and only defoliated plants exhibited declines in mean ramet height. The number of ramets per plant did not decline relative to controls in either species. Thus, these orchids, especiallyCypripedium, appeared to allocate resources preferentially to vegetative growth functions over sexual reproduction. Per-plant variation in leaf and flower number per ramet, as well as in mean ramet height, consistently declined in response to treatment, significantly so in the case of mean ramet height, suggesting that ramets became more similar within genets. These results suggest both similarities and differences in the ways in whichCephalanthera andCypripedium mobilize resources in response to stress.