Emergence of Bulk CsCl Structure in (CsCl)nCs+ Cluster Ions

The emergence of CsCl bulk structure in (CsCl)nCs+ cluster ions is investigated using a mixed quantum-mechanical/semiempirical theoretical approach. We find that rhombic dodecahedral fragments (with bulk CsCl symmetry) are more stable than rock-salt fragments after the completion of the fifth rhombic dodecahedral atomic shell. From this size (n=184) on, a new set of magic numbers should appear in the experimental mass spectra. We also propose another experimental test for this transition, which explicitely involves the electronic structure of the cluster. Finally, we perform more detailed calculations in the size range n=31--33, where recent experimental investigations have found indications of the presence of rhombic dodecahedral (CsCl)32Cs+ isomers in the cluster beams.Comment: LaTeX file. 6 pages and 4 pictures. Accepted for publication in Phys. Rev.

Thermal expansion in small metal clusters and its impact on the electric polarizability

The thermal expansion coefficients of $\mathrm{Na}_{N}$ clusters with $8 \le N \le 40$ and $\mathrm{Al}_{7}$, $\mathrm{Al}_{13}^-$ and $\mathrm{Al}_{14}^-$ are obtained from {\it ab initio} Born-Oppenheimer LDA molecular dynamics. Thermal expansion of small metal clusters is considerably larger than that in the bulk and size-dependent. We demonstrate that the average static electric dipole polarizability of Na clusters depends linearly on the mean interatomic distance and only to a minor extent on the detailed ionic configuration when the overall shape of the electron density is enforced by electronic shell effects. The polarizability is thus a sensitive indicator for thermal expansion. We show that taking this effect into account brings theoretical and experimental polarizabilities into quantitative agreement.Comment: 4 pages, 2 figures, one table. Accepted for publication in Physical Review Letters. References 10 and 23 update

Ab initio many-body calculations on infinite carbon and boron-nitrogen chains

In this paper we report first-principles calculations on the ground-state electronic structure of two infinite one-dimensional systems: (a) a chain of carbon atoms and (b) a chain of alternating boron and nitrogen atoms. Meanfield results were obtained using the restricted Hartree-Fock approach, while the many-body effects were taken into account by second-order M{\o}ller-Plesset perturbation theory and the coupled-cluster approach. The calculations were performed using 6-31$G^{**}$ basis sets, including the d-type polarization functions. Both at the Hartree-Fock (HF) and the correlated levels we find that the infinite carbon chain exhibits bond alternation with alternating single and triple bonds, while the boron-nitrogen chain exhibits equidistant bonds. In addition, we also performed density-functional-theory-based local density approximation (LDA) calculations on the infinite carbon chain using the same basis set. Our LDA results, in contradiction to our HF and correlated results, predict a very small bond alternation. Based upon our LDA results for the carbon chain, which are in agreement with an earlier LDA calculation calculation [ E.J. Bylaska, J.H. Weare, and R. Kawai, Phys. Rev. B 58, R7488 (1998).], we conclude that the LDA significantly underestimates Peierls distortion. This emphasizes that the inclusion of many-particle effects is very important for the correct description of Peierls distortion in one-dimensional systems.Comment: 3 figures (included). To appear in Phys. Rev.

NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction.

The bioenergetics and molecular determinants of the metabolic response to mitochondrial dysfunction are incompletely understood, in part due to a lack of appropriate isogenic cellular models of primary mitochondrial defects. Here, we capitalize on a recently developed cell model with defined levels of m.8993T>G mutation heteroplasmy, mTUNE, to investigate the metabolic underpinnings of mitochondrial dysfunction. We found that impaired utilization of reduced nicotinamide adenine dinucleotide (NADH) by the mitochondrial respiratory chain leads to cytosolic reductive carboxylation of glutamine as a new mechanism for cytosol-confined NADH recycling supported by malate dehydrogenase 1 (MDH1). We also observed that increased glycolysis in cells with mitochondrial dysfunction is associated with increased cell migration in an MDH1-dependent fashion. Our results describe a novel link between glycolysis and mitochondrial dysfunction mediated by reductive carboxylation of glutamine

SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the role of metabolism regulating macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical Th2 cytokine interleukin 4 (IL-4) to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising ROS levels. ROS serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.This work was supported by the British Heart Foundation (RG/18/7/33636), the MRC (MC_UU_00014/2) and the FP7 MITIN (223450). K.P. was a recipient of a fellowship from the Wellcome Trust. A.N.J.M. and E.J. are supported by the Wellcome Trust (100963/Z/13/Z) and the MRC (U105178805). J.L. is a recipient fellowship of the British Heart Foundation. A.D. was a Marie-Curie Early-Stage Researcher supported by the European Union’s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ‘SymBioSys’) to J.S.-R. A.K. is supported by the Wellcome Trust (106260/Z/14/Z) and an ERC award (648889). P.F. is supported by the Science Foundation Ireland (10/IN.1/B3004). The IMS Genomics and Transcriptomics and Histology cores (B.M.-A., B.Y.H.L. and M.K.M.) are funded by the UK MRC Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z). The Disease Model Core is part of the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5) and Wellcome Trust Strategic Award (100574/Z/12/Z)

Optical extinction and scattering cross sections of plasmonic nanoparticle dimers in aqueous suspension

Absolute extinction and scattering cross sections for gold nanoparticle dimers were determined experimentally using a chemometric approach involving singular-value decomposition of the extinction and scattering spectra of slowly aggregating gold nanospheres in aqueous suspension. Quantitative spectroscopic data on plasmonic nanoparticle assemblies in liquid suspension are rare, in particular for particles larger than 40 nm, and in this work we demonstrate how such data can be obtained directly from the aggregating suspension. Our method can analyse, non invasively, the evolution of several sub-populations of nanoparticle assemblies. It may be applied to other self-assembling nanoparticle systems with an evolving optical response. The colloidal systems studied here are based on 20, 50 and 80 nm gold nanospheres in aqueous solutions containing sodium lipoate. In these systems, the reversible dimerisation process can be controlled using pH and ionic strength, and this control is rationalised in terms of DLVO theory. The dimers were identified in suspension by their translational and rotational diffusion through scattering correlation spectroscopy. Moreover, their gigadalton molecular weight was measured using electrospray charge-detection mass spectrometry, demonstrating that mass spectrometry can be used to study nanoparticles assemblies of very high molecular mass. The extinction and scattering cross sections calculated in the discrete-dipole approximation (DDA) agree very well with those obtained experimentally using our approach

Surface reconstruction induced geometries of Si clusters

We discuss a generalization of the surface reconstruction arguments for the structure of intermediate size Si clusters, which leads to model geometries for the sizes 33, 39 (two isomers), 45 (two isomers), 49 (two isomers), 57 and 61 (two isomers). The common feature in all these models is a structure that closely resembles the most stable reconstruction of Si surfaces, surrounding a core of bulk-like tetrahedrally bonded atoms. We investigate the energetics and the electronic structure of these models through first-principles density functional theory calculations. These models may be useful in understanding experimental results on the reactivity of Si clusters and their shape as inferred from mobility measurements.Comment: 9 figures (available from the author upon request) Submitted to Phys. Rev.

Work functions, ionization potentials, and in-between: Scaling relations based on the image charge model

We revisit a model in which the ionization energy of a metal particle is associated with the work done by the image charge force in moving the electron from infinity to a small cut-off distance just outside the surface. We show that this model can be compactly, and productively, employed to study the size dependence of electron removal energies over the range encompassing bulk surfaces, finite clusters, and individual atoms. It accounts in a straightforward manner for the empirically known correlation between the atomic ionization potential (IP) and the metal work function (WF), IP/WF$\sim$2. We formulate simple expressions for the model parameters, requiring only a single property (the atomic polarizability or the nearest neighbor distance) as input. Without any additional adjustable parameters, the model yields both the IP and the WF within $\sim$10% for all metallic elements, as well as matches the size evolution of the ionization potentials of finite metal clusters for a large fraction of the experimental data. The parametrization takes advantage of a remarkably constant numerical correlation between the nearest-neighbor distance in a crystal, the cube root of the atomic polarizability, and the image force cutoff length. The paper also includes an analytical derivation of the relation of the outer radius of a cluster of close-packed spheres to its geometric structure.Comment: Original submission: 8 pages with 7 figures incorporated in the text. Revised submission (added one more paragraph about alloy work functions): 18 double spaced pages + 8 separate figures. Accepted for publication in PR

Structural Transitions and Global Minima of Sodium Chloride Clusters

In recent experiments on sodium chloride clusters structural transitions between nanocrystals with different cuboidal shapes were detected. Here we determine reaction pathways between the low energy isomers of one of these clusters, (NaCl)35Cl-. The key process in these structural transitions is a highly cooperative rearrangement in which two parts of the nanocrystal slip past one another on a {110} plane in a direction. In this way the nanocrystals can plastically deform, in contrast to the brittle behaviour of bulk sodium chloride crystals at the same temperatures; the nanocrystals have mechanical properties which are a unique feature of their finite size. We also report and compare the global potential energy minima for (NaCl)NCl- using two empirical potentials, and comment on the effect of polarization.Comment: extended version, 13 pages, 8 figures, revte

Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling