Highlights ► This review summarizes the effects of glucocorticoids and BDNF on neural plasticity. ► BDNF localization and activation of its receptors are described. ► Trophic effects of ...glucocorticoids are compared in hippocampus and amygdala. ► Interactions with neurotransmitters and other signaling molecules are covered.
Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal ...muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Our previous work on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle and restored contractile function, with affected dogs surviving more than 4 years post injection. This remarkable therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously described canine cohort that showed dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice but also identified transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created metrics to pinpoint potential biomarkers of disease progression and correction.
Mack and colleagues created a novel array of visualization metrics from RNA-sequencing data to quantify disease correction after AAV8-mediated gene transfer. In dogs suffering from X-linked myotubular myopathy and previously treated with increasing doses of recombinant AAV, they showed that transcriptome remodeling correlated with clinical observations, and they identified biomarkers of disease correction.
Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish contain methyl mercury (MeHg), which may harm the developing fetus. U.S. ...government recommendations for women of childbearing age are to modify consumption of high-MeHg fish, while recommendations encourage fish consumption among the general population because of nutritional benefits. To investigate the aggregate impacts of hypothetical shifts in fish consumption, the Harvard Center for Risk Analysis convened an expert panel (see acknowledgments). Effects investigated include prenatal cognitive development, coronary heart disease mortality, and stroke. Substitution of fish with high MeHg concentrations with fish containing less MeHg among women of childbearing age yields substantial developmental benefits and few negative impacts. However, if women instead decrease fish consumption, countervailing risks substantially reduce net benefits. If other adults (mistakenly and inappropriately) also reduce their fish consumption, the net public health impact is negative. Although high compliance with recommended fish consumption patterns can improve public health, unintended shifts in consumption can lead to public health losses. Risk managers should investigate and carefully consider how populations will respond to interventions, how those responses will influence nutrient intake and contaminant exposure, and how these changes will affect aggregate public health.
Atlantic multidecadal variability (AMV) is the term used to describe the pattern of variability in North Atlantic sea surface temperatures (SSTs) that is characterized by decades of basinwide warm or ...cool anomalies, relative to the global mean. AMV has been associated with numerous climate impacts in many regions of the world including decadal variations in temperature and activity, and sea level changes. Given its importance, understanding the physical processes that drive AMV and the extent to which its evolution is predictable is a key challenge in climate science. A leading hypothesis is that natural variations in ocean circulation control changes in ocean heat content and consequently AMV phases. However, this view has been challenged recently by claims that changing natural and anthropogenic radiative forcings are critical drivers of AMV. Others have argued that changes in ocean circulation are not required. Here, we review the leading hypotheses and mechanisms for AMV and discuss the key debates. In particular, we highlight the need for a holistic understanding of AMV. This perspective is a key motivation for a major new U.K. research program: the North Atlantic Climate System Integrated Study (ACSIS), which brings together seven of the United Kingdom’s leading environmental research institutes to enable a broad spectrum approach to the challenges of AMV. ACSIS will deliver the first fully integrated assessment of recent decadal changes in the North Atlantic, will investigate the attribution of these changes to their proximal and ultimate causes, and will assess the potential to predict future changes.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neutrophils are the first and most numerous cells to arrive at the site of an inflammatory insult and are among the first to die. We previously reported that alpha defensins, released from apoptotic ...human neutrophils, augmented the antimicrobial capacity of macrophages while also inhibiting the biosynthesis of proinflammatory cytokines. In vivo, alpha defensin administration protected mice from inflammation, induced by thioglychollate-induced peritonitis or following infection with Salmonella enterica serovar Typhimurium. We have now dissected the antiinflammatory mechanism of action of the most abundant neutrophil alpha defensin, Human Neutrophil Peptide 1 (HNP1). Herein we show that HNP1 enters macrophages and inhibits protein translation without inducing the unfolded-protein response or affecting mRNA stability. In a cell-free in vitro translation system, HNP1 powerfully inhibited both cap-dependent and cap-independent mRNA translation while maintaining mRNA polysomal association. This is, to our knowledge, the first demonstration of a peptide released from one cell type (neutrophils) directly regulating mRNA translation in another (macrophages). By preventing protein translation, HNP1 functions as a “molecular brake” on macrophage-driven inflammation, ensuring both pathogen clearance and the resolution of inflammation with minimal bystander tissue damage.
Data were collected at a wastewater treatment plant (WWTP) in Burlington, Vermont, USA, (serving 30,000 people) to assess the relative contribution of CSO (combined sewer overflow) bypass flows and ...treated wastewater effluent to the load of steroid hormones and other wastewater micropollutants (WMPs) from a WWTP to a lake. Flow-weighted composite samples were collected over a 13 month period at this WWTP from CSO bypass flows or plant influent flows (n = 28) and treated effluent discharges (n = 22). Although CSO discharges represent 10% of the total annual water discharge (CSO plus treated plant effluent discharges) from the WWTP, CSO discharges contribute 40–90% of the annual load for hormones and WMPs with high (>90%) wastewater treatment removal efficiency. By contrast, compounds with low removal efficiencies (<90%) have less than 10% of annual load contributed by CSO discharges. Concentrations of estrogens, androgens, and WMPs generally are 10 times higher in CSO discharges compared to treated wastewater discharges. Compound concentrations in samples of CSO discharges generally decrease with increasing flow because of wastewater dilution by rainfall runoff. By contrast, concentrations of hormones and many WMPs in samples from treated discharges can increase with increasing flow due to decreasing removal efficiency.
This work provides proof of concept for the use of nanosecond repetitively pulsed (NRP) plasma discharges to accelerate a propagating turbulent flame, resulting in enhanced deflagration-to-detonation ...transition and significant reduction in run-up length. The investigations are conducted on a stoichiometric hydrogen-air mixture at near ambient conditions. The effect of plasma actuation on the flame velocity is investigated using time-of-flight measurements of the propagating flame and detonation wave. The flame velocity shortly after the application of the NRP plasma discharges is more than double that obtained in cases in which no plasma is applied. High-speed imaging of OH* chemiluminescence in the electrode area confirms this result and provides insight about the mechanisms of plasma action. While the volumetric energy deposited during plasma actuation is sufficiently low as to not ignite the combustible mixture prior the arrival of the flame, the chemical and thermal enhancement of the gas is efficient enough to significantly accelerate the transition to detonation. The decrease in the run-up length to transition to detonation is obtained for a plasma power of less than 0.14% of the thermal power of the flame. This result indicates that low-energy active devices using NRP discharges might be suitable for replacing passive devices such as orifice plates or Shchelkin spirals.
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