Natural Killer Cells Induce Eosinophil Activation and Apoptosis

Eosinophils are potent inflammatory cells with numerous immune functions, including antigen presentation and exacerbation of inflammatory responses through their capacity to release a range of largely preformed cytokines and lipid mediators. Thus, timely regulation of eosinophil activation and apoptosis is crucial to develop beneficial immune response and to avoid tissue damage and induce resolution of inflammation. Natural Killer (NK) cells have been reported to influence innate and adaptive immune responses by multiple mechanisms including cytotoxicity against other immune cells. In this study, we analyzed the effect of the interaction between NK cells and eosinophils. Co-culture experiments revealed that human NK cells could trigger autologous eosinophil activation, as shown by up-regulation of CD69 and down-regulation of CD62L, as well as degranulation, evidenced by increased CD63 surface expression, secretion of eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN). Moreover, NK cells significantly and dose dependently increased eosinophil apoptosis as shown by annexin V and propidium iodide (PI) staining. Direct contact was necessary for eosinophil degranulation and apoptosis. Increased expression of phosphorylated extracellular signal-regulated kinase (ERK) in cocultured eosinophils and inhibition of eosinophil CD63 expression by pharmacologic inhibitors suggest that MAPK and PI3K pathways are involved in NK cell-induced eosinophil degranulation. Finally, we showed that NK cells increased reactive oxygen species (ROS) expression by eosinophils in co-culture and that mitochondrial inhibitors (rotenone and antimycin) partially diminished NK cell-induced eosinophil apoptosis, suggesting the implication of mitochondrial ROS in NK cell-induced eosinophil apoptosis. Pan-caspase inhibitor (ZVAD-FMK) only slightly decreased eosinophil apoptosis in coculture. Altogether, our results suggest that NK cells regulate eosinophil functions by inducing their activation and their apoptosis.     

Greater initial adaptations to submaximal muscle lengthening than maximal shortening

Hortobágyi, Tibor, Jason Barrier, David Beard, JohnBraspennincx, Peter Koens, Paul Devita, Line Dempsey, and Jean Lambert. Greater initial adaptations to submaximal muscle lengthening thanmaximal shortening. J. Appl. Physiol.81(4): 1677-1682, 1996.The purpose of this study was tocompare the short-term strength and neural adaptations to eccentric andconcentric training at equal force levels. Forty-two sedentary women(age = 21.5 yr) were ranked based on the initial quadriceps strengthscore, and trios of subjects were randomly assigned to either aneccentric (n = 14), a concentric (n = 14), or a nonexercising controlgroup (n = 14). Training involved atotal of 824 eccentric or concentric quadriceps actions at 1.05 rad ^· s¹administered in four sets of 6-10 repetitions, four times per weekfor 6 wk. Before and after training, all subjects were tested forunilateral maximal isometric and eccentric and concentric actions at1.05 rad ^· s¹and for a 40-repetition eccentric and concentric fatigue series of theleft and right quadriceps. Surface electromyographic activity of thevastus lateralis and medialis was monitored during testing. Concentrictraining increased concentric (36%, P < 0.05), isometric (18%, P < 0.05), and eccentric strength (13%), and eccentric training increasedeccentric (42%, P < 0.05),isometric (30%, P < 0.05), andconcentric (13%) strength. Eccentric training improved eccentric andisometric strength more (P < 0.05)than did concentric training. The electromyographic adaptations weregreater with eccentric training. Cross-education was 6%, and neithertraining mode modified fatigability. The data suggest that training ofthe quadriceps muscle with submaximal eccentric actions brings aboutgreater strength adaptations faster than does training withmaximal-level concentric actions in women. This greater adaptation islikely to be mediated by both mechanical and neural factors.

     

An update on the validation of whole slide imaging systems following FDA approval of a system for a routine pathology diagnostic service in the United States

Pathologists have used light microscopes and glass slides to interpret the histologic appearance of normal and diseased tissues for more than 150 years. The quality of both microtomes used to cut tissue sections and microscopes has improved significantly during the past few decades, but the process of rendering diagnoses has changed little. By contrast, major advances in digital technology have occurred since the introduction of hand held electronic devices, including the development of whole slide imaging (WSI) systems with software packages that can convert microscope images into virtual (digital) slides that can be viewed on computer monitors and via the internet. To date, however, these technological developments have had minimal impact on the way pathologists perform their daily work, with the exception of using computers to access electronic medical records and scholarly web sites for pertinent information to assist interpretation of cases. Traditional practice is likely to change significantly during the next decade, especially since the Federal Drug Administration in the USA has approved the first WSI system for routine diagnostic practice. I review here the development and slow acceptance of WSI by pathology departments. I focus on recent advances in validation of WSI systems that is required for routine diagnostic reporting of pathology cases using this technology.     

Evidence that acidosis alters the high-affinity dopamine uptake in rat striatal slices and synaptosomes by different mechanisms partially related to oxidative damage

Several experimental studies have shown that acidosis impairs neurotransmitter uptake processes. The purpose of this study was to determine the mechanism underlying acidosis-induced alterations of the high-affinity dopamine (DA) uptake in rat striatal synaptosomes and slices. Acidosis (pH 5.5) performed either by lactic acid or phosphoric acid induced a decrease in the high-affinity DA uptake in the two striatal models, slices being lesser affected than synaptosomes. Addition of the acid prior to uptake measurement led to a strong reduction of the DA uptake velocity. This early inhibitory effect was completely reversed when acid was removed from the medium by washings. Conversely, when slices and synaptosomes were pre-incubated for different times with each acid, DA uptake remained inhibited in spite of washings. This later inhibition was accompanied by the production of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and was partially prevented by the antioxidant Trolox. Taken together, these results suggest that acidosis, in a degree encountered during ischemia, alters the high-affinity DA uptake by at least two ways: an early and direct effect of H(+) ions on the DA transporters, and subsequently an inhibition partially mediated by free radical damage.     

The up-regulation of the striatal dopamine transporter's activity by cAMP is PKA-, CaMK II- and phosphatase-dependent

The neuronal dopamine transporter (DAT) is a presynaptic plasma membrane protein mediating the re-uptake of dopamine released from synaptic cleft into the nerve terminals. While the regulation of its activity by protein kinase C signalling is well-characterized, there is controversial debate about its regulation by protein kinase A (PKA) signalling. In rat striatal synaptosomes, we showed that a cell-permeable cyclic adenosine 3',5'-monophosphate analogue up-regulated the DAT capacity without modification of its efficiency. This acute effect was PKA-, calcium calmodulin dependent kinase II- and phosphatase-dependent. Together, these results suggest that the activity of DAT may depend on a state of the transporter with both specific phosphorylated and dephosphorylated sites.     

Role of miRNA and miRNA processing factors in development and disease

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 17-24 nucleotides (nt) in length that are encoded in the genomes of plants and animals. The seminal discoveries of miRNA made in C. elegans have led the way to the rampant discoveries being made today in this field. Since each miRNA is predicted and in some cases confirmed to regulate multiple genes, the potential regulatory circuitry afforded by miRNAs is thought to be enormous and could amount to regulation of >30% of all human genes. Due to the sequences of many of the miRNAs being highly homologous among organisms, the huge potential of miRNAs to regulate gene expression, and the hints of miRNAs being useful in both diagnostics and therapeutics, it is no wonder these small RNAs are gaining such popularity in both the academic and industrial settings. It is now becoming clear that the miRNA gene class represents a very important gene regulatory network. This article reviews the initial discoveries of miRNA that began in the nematode C. elegans, and extends into what is known about miRNAs and miRNA processing factors in mouse development and human disease.     

Occurrence of oestrogenic pollutants and widespread feminisation of male tilapia in peri-urban dams in Bulawayo,Zimbabwe

Peri-urban water bodies are at risk from excessive pollution as they are direct sinks for urban effluents. The occurrence of oestrogenic and androgenic endocrine disrupting chemicals (EDCs) in effluents and water bodies around the city of Bulawayo, Zimbabwe, and their effects on wild fish was investigated in 2013. Effluent and water were sampled from sewage treatment plants, an urban stream, and effluent-polluted dams, and were compared with a ‘pristine’ dam upstream of Bulawayo. Organic pollutants were extracted by solid-phase extraction and tested for EDCs using a yeast oestrogen/androgen screen. Oestrogenic and androgenic potencies were expressed as 17β-oestradiol equivalent (EEq) or dihydrotestosterone equivalent (TEq). Tilapia and catfish from the dams were analysed for gonado-somatic indices and testis histopathology. Effluents from STPs, which directly flow into Umguza Dam, had EEq of 33 ng l^?1 and 55 ng l^?1, respectively. Umguza Dam, Khami Dam and Matsheumhlope Stream had EEqs of 237 ng l^–1, 9 ng l^?1 and 2 ng l^?1, respectively. Androgenic activity was detected in only one STP (TEq = 93 ng l^?1). Tilapia sampled from effluent-polluted dams had high incidences of testis-ova, but catfish had no signs of reproductive dysfunction. These findings underscore the need for greater attention to EDCs in developing countries where there is scant literature regarding their occurrence and impacts.     

Ocean iron fertilization may amplify climate change pressures on marine animal biomass for limited climate benefit

Climate change scenarios suggest that large-scale carbon dioxide removal (CDR) will be required to maintain global warming below 2°C, leading to renewed attention on ocean iron fertilization (OIF). Previous OIF modelling has found that while carbon export increases, nutrient transport to lower latitude ecosystems declines, resulting in a modest impact on atmospheric CO₂. However, the interaction of these CDR responses with ongoing climate change is unknown. Here, we combine global ocean biogeochemistry and ecosystem models to show that, while stimulating carbon sequestration, OIF may amplify climate-induced declines in tropical ocean productivity and ecosystem biomass under a high-emission scenario, with very limited potential atmospheric CO₂ drawdown. The ‘biogeochemical fingerprint’ of climate change, that leads to depletion of upper ocean major nutrients due to upper ocean stratification, is reinforced by OIF due to greater major nutrient consumption. Our simulations show that reductions in upper trophic level animal biomass in tropical regions due to climate change would be exacerbated by OIF within ~20 years, especially in coastal exclusive economic zones (EEZs), with potential implications for fisheries that underpin the livelihoods and economies of coastal communities. Any fertilization-based CDR should therefore consider its interaction with ongoing climate-driven changes and the ensuing ecosystem impacts in national EEZs.