Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.

Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression.

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and ß1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.

Role of defects and grain boundaries in the thermal response of wafer-scale hBN films.

With more widespread applications of nanotechnology, heat dissipation in nanoscale devices is becoming a critical issue. We study the thermal response of wafer-scale hexagonal boron nitride (hBN) layers, which find potential applications as ideal substrates in two dimensional devices. Sapphire-supported thin hBN films, 2'' in size and of different thicknesses, were grown using metalorganic vapour phase epitaxy. These large-scale films exhibit wrinkles defects and grain boundaries over their entire area. The shift of [Formula: see text] phonon mode with temperature is analysed by considering the cumulative contribution of anharmonic phonon decay along with lattice thermal expansion, defect, and strain modulation. The study demonstrates that during heat treatment the strain evolution plays a dominating role in governing the characteristics of the wrinkled thinner films. Interestingly we find that both defects and strain determine the spectral line-width of these wafer-scale films. To the end, from Raman line-width, the changes in phonon lifetime in delaminated and as-grown films is estimated. The results suggest the possibility of a reduction in thermal transport in these wafer-scale films compared to their bulk counterpart.

Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth.

The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic.

IDH2 reprograms mitochondrial dynamics in cancer through a HIF-1α-regulated pseudohypoxic state.

The role of mitochondria in cancer continues to be debated and paradoxically implicated in opposing functions in tumor growth and tumor suppression. To understand this dichotomy, we explored the function of mitochondrial isocitrate dehydrogenase (IDH)2, a tricarboxylic acid cycle enzyme mutated in subsets of acute leukemias and gliomas, in cancer. Silencing of IDH2 in prostate cancer cells impaired oxidative bioenergetics, elevated reactive oxygen species (ROS) production, and promoted exaggerated mitochondrial dynamics. This was associated with increased subcellular mitochondrial trafficking, turnover of membrane focal adhesion complexes, and enhanced tumor cell migration and invasion, without changes in cell cycle progression. Mechanistically, loss of IDH2 caused ROS-dependent stabilization of hypoxia-inducible factor-1α in normoxia, which was required for increased mitochondrial trafficking and tumor cell movements. Therefore, IDH2 is a dual regulator of cancer bioenergetics and tumor cell motility. This pathway may reprogram mitochondrial dynamics to differentially adjust energy production or promote tumor cell invasion in response to microenvironment conditions.-Wang, Y., Agarwal, E., Bertolini, I., Ghosh, J. C., Seo, J. H., Altieri, D. C. IDH2 reprograms mitochondrial dynamics in cancer through a HIF-1α-regulated pseudohypoxic state.

Regaining a Spatial Dimension: Mechanically Transferrable Two-Dimensional InAs Nanofins Grown by Selective Area Epitaxy.

We report a method for growing rectangular InAs nanofins with deterministic length, width, and height by dielectric-templated selective-area epitaxy. These freestanding nanofins can be transferred to lay flat on a separate substrate for device fabrication. A key goal was to regain a spatial dimension for device design compared to nanowires, while retaining the benefits of bottom-up epitaxial growth. The transferred nanofins were made into devices featuring multiple contacts for Hall effect and four-terminal resistance studies, as well as a global back-gate and nanoscale local top-gates for density control. Hall studies give a 3D electron density 2.5-5 × 1017 cm-3, corresponding to an approximate surface accumulation layer density 3-6 × 1012 cm-2 that agrees well with previous studies of InAs nanowires. We obtain Hall mobilities as high as 1200 cm2/(V s), field-effect mobilities as high as 4400 cm2/(V s), and clear quantum interference structure at temperatures as high as 20 K. Our devices show excellent prospects for fabrication into more complicated devices featuring multiple ohmic contacts, local gates, and possibly other functional elements, for example, patterned superconductor contacts, that may make them attractive options for future quantum information applications.

PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion.

Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.

Hybrid Nanowire Ion-to-Electron Transducers for Integrated Bioelectronic Circuitry.

A key task in the emerging field of bioelectronics is the transduction between ionic/protonic and electronic signals at high fidelity. This is a considerable challenge since the two carrier types exhibit intrinsically different physics and are best supported by very different materials types-electronic signals in inorganic semiconductors and ionic/protonic signals in organic or bio-organic polymers, gels, or electrolytes. Here we demonstrate a new class of organic-inorganic transducing interface featuring semiconducting nanowires electrostatically gated using a solid proton-transporting hygroscopic polymer. This model platform allows us to study the basic transducing mechanisms as well as deliver high fidelity signal conversion by tapping into and drawing together the best candidates from traditionally disparate realms of electronic materials research. By combining complementary n- and p-type transducers we demonstrate functional logic with significant potential for scaling toward high-density integrated bioelectronic circuitry.

The influence of atmosphere on the performance of pure-phase WZ and ZB InAs nanowire transistors.

We compare the characteristics of phase-pure MOCVD grown ZB and WZ InAs nanowire transistors in several atmospheres: air, dry pure N2 and O2, and N2 bubbled through liquid H2O and alcohols to identify whether phase-related structural/surface differences affect their response. Both WZ and ZB give poor gate characteristics in dry state. Adsorption of polar species reduces off-current by 2-3 orders of magnitude, increases on-off ratio and significantly reduces sub-threshold slope. The key difference is the greater sensitivity of WZ to low adsorbate level. We attribute this to facet structure and its influence on the separation between conduction electrons and surface adsorption sites. We highlight the important role adsorbed species play in nanowire device characterisation. WZ is commonly thought superior to ZB in InAs nanowire transistors. We show this is an artefact of the moderate humidity found in ambient laboratory conditions: WZ and ZB perform equally poorly in the dry gas limit yet equally well in the wet gas limit. We also highlight the vital role density-lowering disorder has in improving gate characteristics, be it stacking faults in mixed-phase WZ or surface adsorbates in pure-phase nanowires.

Value and Anisotropy of the Electron and Hole Mass in Pure Wurtzite InP Nanowires.

The effective mass of electrons and holes in semiconductors is pivotal in determining the dynamics of carriers and their confinement energy in nanostructured materials. Surprisingly, this quantity is still unknown in wurtzite (WZ) nanowires (NWs) made of III-V compounds (e.g., GaAs, InAs, GaP, InP), where the WZ phase has no bulk counterpart. Here, we investigate the magneto-optical properties of InP WZ NWs grown by selective-area epitaxy that provides perfectly ordered NWs featuring high-crystalline quality. The combined analysis of the energy of free exciton states and impurity levels under magnetic field (B up to 29 T) allows us to disentangle the dynamics of oppositely charged carriers from the Coulomb interaction and thus to determine the values of the electron and hole effective mass. By application of B⃗ along different crystallographic directions, we also assess the dependence of the transport properties with respect to the NW growth axis (namely, the WZ c axis). The effective mass of electrons along c is me∥ = (0.078 ± 0.002) m0 (m0 is the electron mass in vacuum) and perpendicular to c is me⊥ = (0.093 ± 0.001) m0, resulting in a 20% mass anisotropy. Holes exhibit a much larger (∼320%) and opposite mass anisotropy with their effective mass along and perpendicular to c equal to mh∥ = (0.81 ± 0.18) m0 and mh⊥ = (0.250 ± 0.016) m0, respectively. While no full consensus is found with current theoretical results on WZ InP, our findings show trends remarkably similar to the experimental data available in WZ bulk materials, such as InN, GaN, and ZnO.

Long-Lived Hot Carriers in III-V Nanowires.

Heat management mechanisms play a pivotal role in driving the design of nanowire (NW)-based devices. In particular, the rate at which charge carriers cool down after an external excitation is crucial for the efficiency of solar cells, lasers, and high-speed transistors. Here, we investigate the thermalization properties of photogenerated carriers by continuous-wave (cw) photoluminescence (PL) in InP and GaAs NWs. A quantitative analysis of the PL spectra recorded up to 310 K shows that carriers can thermalize at a temperature much higher than that of the lattice. We find that the mismatch between carrier and lattice temperature, ΔT, increases exponentially with lattice temperature and depends inversely on the NW diameter. ΔT is instead independent of other NW characteristics, such as crystal structure (wurtzite vs zincblende), chemical composition (InP vs GaAs), shape (tapered vs columnar NWs), and growth method (vapor-liquid-solid vs selective-area growth). Remarkably, carrier temperatures as high as 500 K are reached at the lattice temperature of 310 K in NWs with ∼70 nm diameter. While a population of nonequilibrium carriers, usually referred to as "hot carriers", is routinely generated by high-power laser pulses and detected by ultrafast spectroscopy, it is quite remarkable that it can be observed in cw PL measurements, when a steady-state population of carriers is established. Time-resolved PL measurements show that even in the thinnest NWs carriers have enough time (∼1 ns) after photoexcitation to interact with phonons and thus to release their excess energy. Nevertheless, the inability of carriers to reach a full thermal equilibrium with the lattice points to inhibited phonon emission primarily caused by the large surface-to-volume ratio of small diameter NWs.

Review on photonic properties of nanowires for photovoltaics.

III-V semiconductor nanowires behave as optical antennae because of their shape anisotropy and high refractive index. The antennae like behavior modifies the absorption and emission properties of nanowires compared to planar materials. Nanowires absorb light more efficiently compared to an equivalent volume planar material, leading to higher short circuit current densities. The modified emission from the nanowires has the potential to increase the open circuit voltage from nanowire solar cells compared to planar solar cells. In order to achieve high efficiency nanowire solar cells it is essential to control the surface state density and doping in nanowires. We review the physics of nanowire solar cells and progress made in addressing the surface recombination and doping of nanowires, with emphasis on GaAs and InP materials.

Controlling the exciton emission of gold coated GaAs-AlGaAs core-shell nanowires with an organic spacer layer.

Excitons are the most prominent optical excitations and controlling their emission is an important step towards new optical devices. We have investigated the exciton emission from uncoated and gold/aluminum quinoline (Alq3) coated GaAs-AlGaAs-GaAs core-shell nanowires (NWs) using temperature-, intensity- and polarization dependent photoluminescence (PL). Plasmonic GaAs-AlGaAs-GaAs NWs with a ∼10 nm thick Au coating but without an Alq3 spacer layer reveal a significant reduction of the PL intensity of the exciton emission compared with the uncoated NW sample. Plasmonic NW samples with the same nominal Au coverage and an additional Alq3 interlayer of 3 or 6 nm thickness show a clearly stronger PL intensity which increases with rising Alq3 spacer thickness. Time-resolved (TR) PL measurements reveal an increase of the exciton decay rate by a factor of up to two with decreasing Alq3 spacer thickness suggesting the presence of Förster energy transfer from NW excitons to plasmon oscillations in the gold film. The weak change of the decay time, however, indicates that Förster energy-transfer is only partially responsible for the PL quenching in the gold coated NWs. The main reason for the reduction of the PL emission is attributed to a gold induced band-bending in the GaAs NW core which causes exciton dissociation. With increasing Alq3 spacer thickness the band-bending decreases leading to a reduction of the exciton dissociation and PL quenching. Our interpretation is supported by electron energy loss spectroscopy measurements which show a signal reduction and blue shift of defect (possibly EL2) transitions when gold particles are deposited on NWs compared with bare or Alq3 coated NWs.

Magneto-optical properties of wurtzite-phase InP nanowires.

The possibility to grow in zincblende (ZB) and/or wurtzite (WZ) crystal phase widens the potential applications of semiconductor nanowires (NWs). This is particularly true in technologically relevant III-V compounds, such as GaAs, InAs, and InP, for which WZ is not available in bulk form. The WZ band structure of many III-V NWs has been widely studied. Yet, transport (that is, carrier effective mass) and spin (that is, carrier g-factor) properties are almost experimentally unknown. We address these issues in a well-characterized material: WZ indium phosphide. The value and anisotropy of the reduced mass (µ exc) and g-factor (g exc) of the band gap exciton are determined by photoluminescence measurements under intense magnetic fields (B, up to 28 T) applied along different crystallographic directions. µ exc is 14% greater in WZ NWs than in a ZB bulk reference and it is 6% greater in a plane containing the WZ c axis than in a plane orthogonal to c. The Zeeman splitting is markedly anisotropic with g exc = |ge| = 1.4 for B⊥c (where ge is the electron g-factor) and g exc = |ge - gh,//| = 3.5 for B//c (where gh,// is the hole g-factor). A noticeable B-induced circular dichroism of the emitted photons is found only for B//c, as expected in WZ-phase materials.

Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility.

Mitochondria control bioenergetics and cell fate decisions, but how they influence nuclear gene expression is understood poorly. Here, we show that deletion or reduction in the levels of cyclophilin D (CypD, also called Ppif), a mitochondrial matrix peptidyl prolyl isomerase and apoptosis regulator, results in increased cell proliferation and enhanced cell migration and invasion. These responses are associated with extensive transcriptional changes, modulation of a chemokine/chemokine receptor gene signature, and activation of the pleiotropic inflammatory mediator, STAT3. In the absence of CypD, active STAT3 enhances cell proliferation via accelerated entry into S-phase and stimulates autocrine/paracrine cell motility through Cxcl12-Cxcr4-directed chemotaxis. Therefore, CypD directs mitochondria-to-nuclei inflammatory gene expression in normal and tumor cells. This pathway may contribute to malignant traits under conditions of CypD modulation.

Effect of active region position in Fabry-Perot single transverse mode broad-waveguide InGaAsP/InP lasers.

The dependence of laser performance on the active region position in broad-waveguide laser diodes is presented in this paper. Performance of structures with different position of active region is compared in simulation and actual devices. Lasers with active region displaced towards the p-cladding layer outperformed the lasers with active region undisplaced or displaced towards the n-cladding layer both in simulation and experimentally. Maximum output power increased by 25% for devices with active region displaced towards the p-cladding layer.

Enhanced minority carrier lifetimes in GaAs/AlGaAs core-shell nanowires through shell growth optimization.

The effects of AlGaAs shell thickness and growth time on the minority carrier lifetime in the GaAs core of GaAs/AlGaAs core-shell nanowires grown by metal-organic chemical vapor deposition are investigated. The carrier lifetime increases with increasing AlGaAs shell thickness up to a certain value as a result of reducing tunneling probability of carriers through the AlGaAs shell, beyond which the carrier lifetime reduces due to the diffusion of Ga-Al and/or impurities across the GaAs/AlGaAs heterointerface. Interdiffusion at the heterointerface is observed directly using high-angle annular dark field scanning transmission electron microscopy. We achieve room temperature minority carrier lifetimes of 1.9 ns by optimizing the shell growth with the intention of reducing the effect of interdiffusion.

Merged beam laser design for reduction of gain-saturation and two-photon absorption in high power single mode semiconductor lasers.

In this paper we report a method to overcome the limitations of gain-saturation and two-photon absorption faced by developers of high power single mode InP-based lasers and semiconductor optical amplifiers (SOA) including those based on wide-waveguide or slab-coupled optical waveguide laser (SCOWL) technology. The method is based on Y-coupling design of the laser cavity. The reduction in gain-saturation and two-photon absorption in the merged beam laser structures (MBL) are obtained by reducing the intensity of electromagnetic field in the laser cavity. Standard ridge-waveguide lasers and MBLs were fabricated, tested and compared. Despite a slightly higher threshold current, the reduced gain-saturation in MBLs results in higher output power. The MBLs also produced a single spatial mode, as well as a strongly dominating single spectral mode which is the inherent feature of MBL-type cavity.

High vertical yield InP nanowire growth on Si(111) using a thin buffer layer.

We demonstrate the growth of InP nanowires on Si(111) using a thin InP buffer layer. The buffer layer is grown using a two-step procedure. The initial layer formation is ensured by using a very low growth temperature. An extremely high V/III ratio is necessary to prevent In droplet formation at this low temperature. The second layer is grown on the initial layer at a higher temperature and we find that post-growth annealing of the buffer layer does not improve its crystal quality significantly. It is found that the layers inherently have the (111)B polarity. Nanowires grown on this buffer layer have the same morphology and optical properties as nanowires grown on InP (111)B substrates. The vertical yield of the nanowires grown on the buffer layer is over 97% and we also find that crystal defects in the buffer layer do not affect the morphology, vertical yield or optical properties of the nanowires significantly.

A biomimetic approach towards synthesis of zinc oxide nanoparticles.

Using natural processes as inspiration, the present study demonstrates a positive correlation between zinc metal tolerance ability of a soil fungus and its potential for the synthesis of zinc oxide (ZnO) nanoparticles. A total of 19 fungal cultures were isolated from the rhizospheric soils of plants naturally growing at a zinc mine area in India and identified on the genus, respectively the species level. Aspergillus aeneus isolate NJP12 has been shown to have a high zinc metal tolerance ability and a potential for extracellular synthesis of ZnO nanoparticles under ambient conditions. UV-visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction analysis, transmission electron microscopy, and energy dispersive spectroscopy studies further confirmed the crystallinity, morphology, and composition of synthesized ZnO nanoparticles. The results revealed the synthesis of spherical nanoparticles coated with protein molecules which served as stabilizing agents. Investigations on the role of fungal extracellular proteins in the synthesis of nanoparticles indicated that the process is nonenzymatic but involves amino acids present in the protein chains.