Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT)

Cancer cells rewire their metabolism to support proliferation, growth and survival. In metastatic melanoma the BRAF oncogenic pathway is a master regulator of this process, highlighting the importance of metabolic reprogramming in the pathogenesis of this tumor and offering potential therapeutic approaches. Metabolic adaptation of melanoma cells generally requires increased amounts of NAD+, an essential redox cofactor in cellular metabolism and a signaling molecule. Nicotinamide phosphoribosyltransferase (NAMPT) is the most important NAD+ biosynthetic enzyme in mammalian cells and a direct target of the BRAF oncogenic signaling pathway. These findings suggest that NAMPT is an attractive new therapeutic target, particularly in combination strategies with BRAF or MEK inhibitors. Here we review current knowledge on how oncogenic signaling reprograms metabolism in BRAF-mutated melanoma, and discuss how NAMPT/NAD+ axis contributes to these processes. Lastly, we present evidence supporting a role of NAMPT as a novel therapeutic target in metastatic melanoma

Influence of the conductivity on spin wave propagation in a Permalloy waveguide

This is the final version. Available from AIP Publishing via the DOI in this recordThe influence of the electrical conductivity of a Permalloy waveguide on the spin wave propagation was investigated using the finite-element solution of the combined system of quasistatic electromagnetic potential and linearized LLG (Landau–Lifshitz–Gilbert) equations. The difference in the group velocity between the conductive and nonconductive waveguides becomes large for films over 300 nm thick, and the difference is very small for film thicknesses less than 100 nm. The observed enhancement of the group velocity with increasing film thickness is attributed to the damping caused by the electrical conductivity, which leads to narrowing of the spin wave packet envelope and shorter arrival times of propagating waves. The basic characteristics of the dispersion relations do not change between conductive and nonconductive films for small film thicknesses less than 300 nm. The simulated dispersion relations indicate shift of their maximum intensity toward lower wavenumbers and, therefore, increase in the group velocity with increasing thickness. The simulated decay length of the spin waves for conductive films initially increases but then decreases with increasing thickness, which agrees well with the experimental results. The extracted damping coefficients from both simulations and the experiment agree very well and increase proportionally with d2, where d is the film thickness, due to the additional eddy current damping. The observed thickness and conductivity dependence of spin wave propagation is crucial for magnonics research and toward the development of future spin wave devices using metal films.JSPS KAKENHICentral Research Institute of Fukuoka Universit

Adapting Urban Water Systems to Manage Scarcity in the 21st Century: The Case of Los Angeles.

Acute water shortages for large metropolitan regions are likely to become more frequent as climate changes impact historic precipitation levels and urban population grows. California and Los Angeles County have just experienced a severe four year drought followed by a year of high precipitation, and likely drought conditions again in Southern California. We show how the embedded preferences for distant sources, and their local manifestations, have created and/or exacerbated fluctuations in local water availability and suboptimal management. As a socio technical system, water management in the Los Angeles metropolitan region has created a kind of scarcity lock-in in years of low rainfall. We come to this through a decade of coupled research examining landscapes and water use, the development of the complex institutional water management infrastructure, hydrology and a systems network model. Such integrated research is a model for other regions to unpack and understand the actual water resources of a metropolitan region, how it is managed and potential ability to become more water self reliant if the institutions collaborate and manage the resource both parsimoniously, but also in an integrated and conjunctive manner. The Los Angeles County metropolitan region, we find, could transition to a nearly water self sufficient system

Free N-heterocyclic carbenes from Brønsted acidic ionic liquids: Direct detection by electrospray ionization mass spectrometry

Rationale: The occurrence of N-heterocyclic carbenes in imidazolium-based ionic liquids has long been discussed, but no spectroscopic evidence has been reported yet due to their transient nature. The insertion of an ionizable acid group into the cation scaffold of an ionic liquid which acts as a charge tag allows for the direct detection of free carbenes by mass spectrometry. Methods: Three different Brønsted acidic ionic liquids were synthesized: 1-methyl-3-carboxymethylimidazolium chloride (MAICl), 1-methyl-3-carboxymethylimidazolium acetate (MAIAc) and the corresponding 2-(3-methyl-1H-imidazol-3-ium-1-yl)acetate zwitterion (MAI - H). The speciation of these compounds was then analysed by electrospray ionization ion-trap mass spectrometry in the negative ion mode. Results: The C2-H deprotonation of the imidazolium cation leading to the formation of the corresponding carbene is highly affected by the basic properties of the counter-anion. In the case of MAICl and MAI - H ionic liquids, no charged species corresponding to the free N-heterocyclic carbene was detected. On the contrary, in the presence of a sufficiently basic anion, such as acetate of MAIAc ionic liquid, an intense signal related to the free carbenic species was observed without the addition of an external base. Conclusions: In situ formation of free N-heterocyclic carbenes from Brønsted acidic ionic liquids was demonstrated, highlighting the crucial role of anion basicity in promoting the C2-H proton abstraction from imidazolium cations with a carboxylic side chain.Rationale The occurrence of N-heterocyclic carbenes in imidazolium-based ionic liquids has long been discussed, but no spectroscopic evidence has been reported yet due to their transient nature. The insertion of an ionizable acid group into the cation scaffold of an ionic liquid which acts as a charge tag allows for the direct detection of free carbenes by mass spectrometry. Methods Three different Bronsted acidic ionic liquids were synthesized: 1-methyl-3-carboxymethylimidazolium chloride (MAICl), 1-methyl-3-carboxymethylimidazolium acetate (MAIAc) and the corresponding 2-(3-methyl-1H-imidazol-3-ium-1-yl)acetate zwitterion (MAI - H). The speciation of these compounds was then analysed by electrospray ionization ion-trap mass spectrometry in the negative ion mode. Results The C2-H deprotonation of the imidazolium cation leading to the formation of the corresponding carbene is highly affected by the basic properties of the counter-anion. In the case of MAICl and MAI - H ionic liquids, no charged species corresponding to the free N-heterocyclic carbene was detected. On the contrary, in the presence of a sufficiently basic anion, such as acetate of MAIAc ionic liquid, an intense signal related to the free carbenic species was observed without the addition of an external base. Conclusions In situ formation of free N-heterocyclic carbenes from Bronsted acidic ionic liquids was demonstrated, highlighting the crucial role of anion basicity in promoting the C2-H proton abstraction from imidazolium cations with a carboxylic side chain

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions. Is endogenous oxytocin implicated in emotion discrimination? Ferretti, Maltese et al. demonstrate that oxytocin signaling in the central amygdala plays a key role in the ability of mice to discriminate unfamiliar conspecifics based on their emotional state, both in physiological and genetically determined pathological conditions