Internal gravity waves, the subsurface analogue of the familiar surface gravity waves that break on beaches, are ubiquitous in the ocean. Because of their strong vertical and horizontal currents, and ...the turbulent mixing caused by their breaking, they affect a panoply of ocean processes, such as the supply of nutrients for photosynthesis, sediment and pollutant transport and acoustic transmission; they also pose hazards for man-made structures in the ocean. Generated primarily by the wind and the tides, internal waves can travel thousands of kilometres from their sources before breaking, making it challenging to observe them and to include them in numerical climate models, which are sensitive to their effects. For over a decade, studies have targeted the South China Sea, where the oceans' most powerful known internal waves are generated in the Luzon Strait and steepen dramatically as they propagate west. Confusion has persisted regarding their mechanism of generation, variability and energy budget, however, owing to the lack of in situ data from the Luzon Strait, where extreme flow conditions make measurements difficult. Here we use new observations and numerical models to (1) show that the waves begin as sinusoidal disturbances rather than arising from sharp hydraulic phenomena, (2) reveal the existence of >200-metre-high breaking internal waves in the region of generation that give rise to turbulence levels >10,000 times that in the open ocean, (3) determine that the Kuroshio western boundary current noticeably refracts the internal wave field emanating from the Luzon Strait, and (4) demonstrate a factor-of-two agreement between modelled and observed energy fluxes, which allows us to produce an observationally supported energy budget of the region. Together, these findings give a cradle-to-grave picture of internal waves on a basin scale, which will support further improvements of their representation in numerical climate predictions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Internal gravity waves, the subsurface analogue of the familiar surface gravity waves that break on beaches, are ubiquitous in the ocean. Because of their strong vertical and horizontal currents, and ...the turbulent mixing caused by their breaking, they affect a panoply of ocean processes, such as the supply of nutrients for photosynthesis, sediment and pollutant transport and acoustic transmission; they also pose hazards for man-made structures in the ocean. Generated primarily by the wind and the tides, internal waves can travel thousands of kilometres from their sources before breaking, making it challenging to observe them and to include them in numerical climate models, which are sensitive to their effects. For over a decade, studies have targeted the South China Sea, where the oceans' most powerful known internal waves are generated in the Luzon Strait and steepen dramatically as they propagate west. Confusion has persisted regarding their mechanism of generation, variability and energy budget, however, owing to the lack of in situ data from the Luzon Strait, where extreme flow conditions make measurements difficult. Here we use new observations and numerical models to (1) show that the waves begin as sinusoidal disturbances rather than arising from sharp hydraulic phenomena, (2) reveal the existence of .200- metre-high breaking internal waves in the region of generation that give rise to turbulence levels .10,000 times that in the open ocean, (3) determine that the Kuroshio western boundary current noticeably refracts the internal wave field emanating from the Luzon Strait, and (4) demonstrate a factor-of-two agreement between modelled and observed energy fluxes, which allows us to produce an observationally supported energy budget of the region. Together, these findings give a cradle-to-grave picture of internal waves on a basin scale, which will support further improvements of their representation in numerical climate predictions.
Science as Practice and Culture explores one of the newest and most controversial developments within the rapidly changing field of science studies: the move toward studying scientific practice—the ...work of doing science—and the associated move toward studying scientific culture, understood as the field of resources that practice operates in and on. Andrew Pickering has invited leading historians, philosophers, sociologists, and anthropologists of science to prepare original essays for this volume. The essays range over the physical and biological sciences and mathematics, and are divided into two parts. In part I, the contributors map out a coherent set of perspectives on scientific practice and culture, and relate their analyses to central topics in the philosophy of science such as realism, relativism, and incommensurability. The essays in part II seek to delineate the study of science as practice in arguments across its borders with the sociology of scientific knowledge, social epistemology, and reflexive ethnography.
Abstract
Background
The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and ...plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD).
Method
We investigate proteasome augmentation through overexpression of a rate limiting proteasome subunit and treatment with proteasome activating peptidomimetics developed by our team in hAPP(J20) mice, MC65 cells overexpressing a C99 fragment of APP and elav‐GS‐GAL4>UAS‐APP;UAS‐BACE1 fly models of AD.
Result
We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal‐specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT‐based proteasome‐activating peptidomimetics that stably penetrated the blood‐brain barrier and enhanced 20
S
/26
S
proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models.
Conclusion
We demonstrate proteasome modulation as a viable target for prevention of AD‐like deficits and present a set of novel proteasome agonists as AD therapeutics
The Ontological Turn Pickering, Andrew
Social analysis,
06/2017, Letnik:
61, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In this article I discuss different scientific and non-modern worlds as they appear in a performative (rather than representational) idiom, situating my analysis in relation to the recent ontological ...turns in science and technology studies (STS) and anthropology. I propose an ontology of decentered becoming that can help us take seriously the multiplicity of ‘found’ ontologies. A key concept is that of ‘islands of stability’, which enables a comparative transition between the worlds of science and shamanism. This offers an opportunity to reflect back critically and politically on modernity, while highlighting the problems of anthropological translation that surface in a performative apprehension of non-modern worlds. In conclusion, I touch on scientific and nonscientific worlds (complexity theory, cybernetics, Taoism, Zen) that do not center themselves on islands of stability.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation‐induced ...signaling in lymphocytes; however, little is known of its role in non‐lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine‐induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti‐CD45RB antibody (Bra11) down‐modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 ± 10 % and 47 + 9 % of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11‐induced down‐modulation of CXCR1 and CXCR2. Furthermore, Bra11 treated PMN were functionally inhibited in their capacity to exhibit IL‐8‐induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N‐formyl‐Met‐Leu‐Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL‐8‐mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54‐ to 60‐kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.
Background
The proteasome has key roles in neuronal proteostasis, including removal of misfolded or oxidized proteins, presynaptic protein turnover, as well as synaptic efficacy and plasticity. ...Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). Artificial impairment of proteasome function can mimic many neurodegenerative phenotypes.
Methods
We created transgenic mice and flies as well as novel proteasome activating drugs to examine whether proteasome augmentation can reduce AD like symptoms in animal models of the disease.
Results
We report that manipulation of proteasome activity can influence the rate of AD‐like progression. We show that augmentation of proteasome function in fly and cell culture models of AD delays mortality, cell death, and AD‐like cognitive deficits. We developed a transgenic mouse with neuronal‐specific proteasome overexpression which, when crossed with a mouse model of AD, reduced mortality and diminished AD‐like cognitive deficits. To establish translational relevance, we developed a set of novel proteasome‐activating peptidomimetics based on modifications of proteasome binding fragments derived from the viral protein HIV‐1 Tat. These agonists stably penetrate the blood‐brain‐barrier and enhance 20S as well as 26S proteasome activity. We show that treatment with these agonists protects against cell death in a cell culture model of AD as well as both cognitive decline and mortality in fly and mouse models of AD. The protective effects observed from proteasome overexpression in our models appear to be driven at least in part by increased turnover of the amyloid precursor protein (APP) and β‐secretase enzyme (BACE1) by the proteasome.
Conclusion
We conclude that the proteasome plays an important role in AD‐like progression. Furthermore augmentation of proteasome function is protective against AD‐like pathogenesis in diverse models of the disease, potentially representing a new therapeutic target for treatment of AD.
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