The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes

Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leucodystrophies Canavan's disease and Pelizaeus-Merzbacher-like disease. NAAG and NAA can activate and antagonize neuronal N-methyl-D-aspartate (NMDA) receptors, and also act on group II metabotropic glutamate receptors. Oligodendrocytes and their precursors have recently been shown to express NMDA receptors, and activation of these receptors in ischaemia leads to the death of oligodendrocyte precursors and the loss of myelin. This raises the possibility that the failure to develop myelin, or demyelination, occurring in the leucodystrophies could reflect an action of NAAG or NAA on oligodendrocyte NMDA receptors. However, since the putative subunit composition of NMDA receptors on oligodendrocytes differs from that of neuronal NMDA receptors, the effects of NAAG and NAA on them are unknown. We show that NAAG, but not NAA, evokes an inward membrane current in cerebellar white matter oligodendrocytes, which is reduced by NMDA receptor block (but not by block of metabotropic glutamate receptors). The size of the current evoked by NAAG, relative to that evoked by NMDA, was much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in [Ca^{2+}]i in neurons but not in oligodendrocytes. These differences in the effect of NAAG on oligodendrocytes and neurons may reflect the aforementioned difference in receptor subunit composition. In addition, as a major part of the response in oligodendrocytes was blocked by tetrodotoxin (TTX), much of the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors. Six hours exposure to 1 mM NAAG did not lead to the death of cells in the white matter. We conclude that an action of NAAG on oligodendrocyte NMDA receptors is unlikely to be a major contributor to white matter damage in the leucodystrophies

The oxidizing power of the dark side: Rapid nocturnal aging of biomass burning as an overlooked source of oxidized organic aerosol

Oxidized organic aerosol (OOA) is a major component of ambient particulate matter, substantially affecting both climate and human health. A considerable body of evidence has established that OOA is readily produced in the presence of daylight, thus leading to the association of high concentrations of OOA in the summer or mid-afternoon. However, this current mechanistic understanding fails to explain elevated OOA concentrations during night or wintertime periods of low photochemical activity, thus leading atmospheric models to under predict OOA concentrations by a factor of 3-5. Here we show that fresh emissions from biomass burning rapidly forms OOA in the laboratory over a few hours and without any sunlight. The resulting OOA chemical composition is consistent with the observed OOA in field studies in major urban areas. To estimate the contribution of nocturnally aged OOA in the ambient atmosphere, we incorporate this nighttime-aging mechanism into a chemical-transport model and find that over much of the United States greater than 75% of the OOA formed from fresh biomass burning emissions underwent nighttime aging processes. Thus, the conceptual framework that OOA is predominantly formed in the presence of daylight fails to account for a substantial and rapid oxidation process occurring in the dark

Certainty relations between local and nonlocal observables

We demonstrate that for an arbitrary number of identical particles, each defined on a Hilbert-space of arbitrary dimension, there exists a whole ladder of relations of complementarity between local, and every conceivable kind of joint (or nonlocal) measurements. E.g., the more accurate we can know (by a measurement) some joint property of three qubits (projecting the state onto a tripartite entangled state), the less accurate some other property, local to the three qubits, become. We also show that the corresponding complementarity relations are particularly tight for particles defined on prime dimensional Hilbert spaces.Comment: 4 pages, no figure

Activation of JNK1 contributes to dystrophic muscle pathogenesis

AbstractDuchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product [1, 2]. Subsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood [3]. Dystrophin provides a structural base for the assembly of an integral membrane protein complex [4]. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage [5–7]. However, the development of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models [8, 9]. Although activation of a detrimental signal transduction pathway has been suggested as a probable cause, a specific cellular cascade has yet to be defined. Here, it is shown that murine models of DMD displayed a muscle-specific activation of JNK1. Independent activation of JNK1 resulted in defects in myotube viability and integrity in vitro, similar to a dystrophic phenotype. In addition, direct muscle injection of an adenoviral construct containing the JNK1 inhibitory protein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated signal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis

To other planets with upgraded millennial kombucha in rhythms of sustainability and health support

Humankind has entered a new era of space exploration: settlements on other planetary bodies are foreseen in the near future. Advanced technologies are being developed to support the adaptation to extraterrestrial environments and, with a view on the longer term, to support the viability of an independent economy. Biological processes will likely play a key role and lead to the production of life-support consumables, and other commodities, in a way that is cheaper and more sustainable than exclusively abiotic processes. Microbial communities could be used to sustain the crews’ health as well as for the production of consumables, for waste recycling, and for biomining. They can self-renew with little resources from Earth, be highly productive on a per-volume basis, and be highly versatile—all of which will be critical in planetary outposts. Well-de!ned, semi-open, and stress-resistant microecosystems are particularly promising. An instance of it is kombucha, known worldwide as a microbial association that produces an eponymous, widespread soft drink that could be valuable for sustaining crews’ health or as a synbiotic (i.e., probiotic and prebiotic) after a rational assemblage of de!ned probiotic bacteria and yeasts with endemic or engineered cellulose producers. Bacterial cellulose products offer a wide spectrum of possible functions, from leather-like to innovative smart materials during long-term missions and future activities in extraterrestrial settlements. Cellulose production by kombucha is zero-waste and could be linked to bioregenerative life support system (BLSS) loops. Another advantage of kombucha lies in its ability to mobilize inorganic ions from rocks, which may help feed BLSS from local resources. Besides outlining those applications and others, we discuss needs for knowledge and other obstacles, among which is the biosafety of microbial producers

Normalizing single-cell RNA sequencing data: challenges and opportunities

Single-cell transcriptomics is becoming an important component of the molecular biologist's toolkit. A critical step when analyzing data generated using this technology is normalization. However, normalization is typically performed using methods developed for bulk RNA sequencing or even microarray data, and the suitability of these methods for single-cell transcriptomics has not been assessed. We here discuss commonly used normalization approaches and illustrate how these can produce misleading results. Finally, we present alternative approaches and provide recommendations for single-cell RNA sequencing users

Cancer-associated cells release citrate to support tumour metastatic progression

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter’s major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression