Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

Background Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen‐activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance. Objectives To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy. Methods Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib‐induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib‐resistant melanoma cell survival and invasion, respectively. Results CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF‐mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271‐expressing subpopulations. Trametinib‐induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271‐expressing melanoma subpopulations with RNA interference and small‐molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents – including Δ9‐tetrahydrocannabinol and Vps34 – reduced survival of MEKi‐resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi‐resistant cells in an in vivo zebrafish xenograft. Conclusions These results highlight a novel mechanism of MEKi‐induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug‐resistant melanoma cells to the cytotoxic effects of MEKi

The lithium isotope ratio in the metal-poor halo star G271-162 from VLT/UVES observations

A high resolution (lambda /Delta lambda =~ 110 000), very high S/N (>~ 600) spectrum of the metal-poor turnoff star G 271-162 has been obtained in connection with the commissioning of UVES at VLT/Kueyen. Using both 1D hydrostatic and 3D hydrodynamical model atmospheres, the lithium isotope ratio has been estimated from the \ion{Li}{i},670.8 nm line by means of spectral synthesis. The necessary stellar line broadening (1D: macroturbulence + rotation, 3D: rotation) has been determined from unblended \ion{K}{i}, \ion{Ca}{i} and \ion{Fe}{i} lines. The 3D line profiles agree very well with the observed profiles, including the characteristic line asymmetries. Both the 1D and 3D analyses reveal a possible detection of \element[][6]{Li} in G 271-162, element [][6]{Li}/element [][7]{Li} = 0.02+/-0.01 (1sigma ). It is discussed if the smaller amount of \element[][6]{Li} in G 271-162 than in the similar halo star HD 84937 could be due to differences in stellar mass and/or metallicity or whether it may reflect an intrinsic scatter of \element[][6]{Li}/\element[][7]{Li} in the ISM at a given metallicity. Based on public data released from the UVES commissioning at the VLT/Kueyen telescope, ESO, Paranal, Chile

On bird species diversity and remote sensing – utilizing lidar and hyperspectral data to assess the role of vegetation structure and foliage characteristics as drivers of avian diversity

Avian diversity has long been used as a surrogate for overall diversity. In forest ecosystems, it has been assumed that vegetation structure, composition and condition have a significant impact on avian diversity. Today, these features can be assessed via remote sensing. This study examined how structure metrics from lidar data and narrowband indices from hyperspectral data relate with avian diversity. This was assessed in four deciduous-dominated woods with differing age and structure set in an agricultural matrix in eastern England. The woods were delineated into cells within which metrics of avian diversity and remote sensing based predictors were calculated. Best subset regression was used to obtain best lidar models, hyperspectral models and finally, the best models combining variables from both datasets. The aims were not only to examine the drivers of avian diversity, but to assess the capabilities of the two remote sensing techniques for the task. The amount of understorey vegetation was the best single predictor, followed by Foliage Height Diversity, reflectance at 830 nm, Anthocyanin Reflectance Index 1 and Vogelmann Red Edge Index 2. This showed the significance of the full vertical profile of vegetation, the condition of the upper canopy, and potentially tree species composition. The results thus agree with the role that vegetation structure, condition and floristics are assumed to have for diversity. However, the inclusion of hyperspectral data resulted in such minor improvements to models that its collection for these purposes should be assessed critically

Correlation Time-of-flight Spectrometry of Ultracold Neutrons

The fearures of the correlation method used in time-of-flight spectrometry of ultracold neutrons are analyzed. The time-of-flight spectrometer for the energy range of ultracold neutrons is described, and results of its testing by measuring spectra of neutrons passing through interference filters are presented.Comment: 16 pages, 5 figure

Subthreshold dynamics of the neural membrane potential driven by stochastic synaptic input

In the cerebral cortex, neurons are subject to a continuous bombardment of synaptic inputs originating from the network's background activity. This leads to ongoing, mostly subthreshold membrane dynamics that depends on the statistics of the background activity and of the synapses made on a neuron. Subthreshold membrane polarization is, in turn, a potent modulator of neural responses. The present paper analyzes the subthreshold dynamics of the neural membrane potential driven by synaptic inputs of stationary statistics. Synaptic inputs are considered in linear interaction. The analysis identifies regimes of input statistics which give rise to stationary, fluctuating, oscillatory, and unstable dynamics. In particular, I show that (i) mere noise inputs can drive the membrane potential into sustained, quasiperiodic oscillations (noise-driven oscillations), in the absence of a stimulus-derived, intraneural, or network pacemaker; (ii) adding hyperpolarizing to depolarizing synaptic input can increase neural activity (hyperpolarization-induced activity), in the absence of hyperpolarization-activated currents

Evolution of the electronic structure with size in II-VI semiconductor nanocrystals

In order to provide a quantitatively accurate description of the band gap variation with sizes in various II-VI semiconductor nanocrystals, we make use of the recently reported tight-binding parametrization of the corresponding bulk systems. Using the same tight-binding scheme and parameters, we calculate the electronic structure of II-VI nanocrystals in real space with sizes ranging between 5 and 80 {\AA} in diameter. A comparison with available experimental results from the literature shows an excellent agreement over the entire range of sizes.Comment: 17 pages, 4 figures, accepted in Phys. Rev.

Listen to Nice

In describing Humphrey Jennings’ wartime documentary propaganda film, 'Listen to Britain' (1942), a film with an overtly poetic sensibility and dominantly musical soundtrack, John Corner asserts that ‘through listening to Britain, we are enabled to properly look at it'. This idea of sound leading our attention to the images has underpinned much of the collaborative work between composer and sound designer, Geoffrey Cox, and documentary filmmaker, Keith Marley. It is in this context that the article will analyse an extract of A Film About Nice (Marley and Cox 2010), a contemporary re-imagining of Jean Vigo’s silent documentary, 'A propos de Nice' (1930). Reference will be made throughout to the historical context, and the filmic and theoretical influences that have informed the way music and creative sound design have been used to place emphasis on hearing a place, as much as seeing it

Advances in ab-initio theory of Multiferroics. Materials and mechanisms: modelling and understanding

Within the broad class of multiferroics (compounds showing a coexistence of magnetism and ferroelectricity), we focus on the subclass of "improper electronic ferroelectrics", i.e. correlated materials where electronic degrees of freedom (such as spin, charge or orbital) drive ferroelectricity. In particular, in spin-induced ferroelectrics, there is not only a {\em coexistence} of the two intriguing magnetic and dipolar orders; rather, there is such an intimate link that one drives the other, suggesting a giant magnetoelectric coupling. Via first-principles approaches based on density functional theory, we review the microscopic mechanisms at the basis of multiferroicity in several compounds, ranging from transition metal oxides to organic multiferroics (MFs) to organic-inorganic hybrids (i.e. metal-organic frameworks, MOFs)Comment: 22 pages, 9 figure

Observation of Orbitally Excited B_s Mesons

We report the first observation of two narrow resonances consistent with states of orbitally excited (L=1) B_s mesons using 1 fb^{-1} of ppbar collisions at sqrt{s} = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We use two-body decays into K^- and B^+ mesons reconstructed as B^+ \to J/\psi K^+, J/\psi \to \mu^+ \mu^- or B^+ \to \bar{D}^0 \pi^+, \bar{D}^0 \to K^+ \pi^-. We deduce the masses of the two states to be m(B_{s1}) = 5829.4 +- 0.7 MeV/c^2 and m(B_{s2}^*) = 5839.7 +- 0.7 MeV/c^2.Comment: Version accepted and published by Phys. Rev. Let