Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer1, is characterized by elevated glycogen and fat deposition2. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia inducible factors (HIFs)3, secondary to von hippel-lindau (VHL) mutations that occur in over 90% of ccRCC tumours4. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation5, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed loss of several chromatin remodelling enzymes in a subset of ccRCC (polybromo 1 [PBRM1] ~40%, SET domain containing 2 [SETD2] ~15%, BRCA1 associated protein-1 [BAP1] ~15%, etc.)6–9, indicating that epigenetic perturbations are likely important contributors to the natural history of this disease. Here we utilized an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis, and determined that the gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1)10 is uniformly depleted in over six hundred ccRCC tumours examined. Importantly, the human FBP1 locus resides on chromosome 9q22, whose loss is associated with poor prognosis for ccRCC patients11. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms: 1) FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin12, thereby inhibiting a potential “Warburg effect”13,14, and 2) in pVHL-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis, and the pentose phosphate pathway in a catalytic activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF “inhibitory domain”. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously-identified tumour suppressors (PBRM1, SETD2, BAP1, etc.) which are not consistently mutated in all tumours6,7,15.

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cel-

Two hallmarks of clear cell renal cell carcinoma (ccRCC) are constitutive hypoxia inducible factor (HIF) signaling and abundant intracellular lipid droplets (LDs). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF-2α, but not HIF-1α, activation. HIF-2α dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2 dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF-2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.

The electron-phonon interaction is well known to create major resistance to electron transport in metals and semiconductors, whereas fewer studies are directed to its effect on phonon transport, especially in semiconductors. We calculate the phonon lifetimes due to scattering with electrons (or holes), combine them with the intrinsic lifetimes due to the anharmonic phonon-phonon interaction, all from first principles, and evaluate the effect of the electron-phonon interaction on the lattice thermal conductivity of silicon. Unexpectedly, we find a significant reduction of the lattice thermal conductivity at room temperature as the carrier concentration goes above 10 19 cm −3 (the reduction reaches up to 45% in p-type silicon at around 10 21 cm −3 ), a range of great technological relevance to thermoelectric materials. The coordinates of electrons and atomic nuclei represent the most common degrees of freedom in a solid. The full quantum mechanical treatment of the excitations in a solid thus requires the solution of the Schrödinger equation involving the coordinates of all electrons and atomic nuclei, which appears intractable in most cases. A widely applied simplification, the Born-Oppenheimer approximation (BOA) [1], makes use of the fact that the electrons' mass is much smaller than that of the nuclei, and the electrons respond to the motions of the nuclei so quickly that the nuclei can be treated as static at each instant. Under the BOA, the coordinates of the nuclei enter the electronic Schrödinger equation as external parameters, and in turn the electronic ground-state energy acts as part of the interaction energy between the nuclei given a specific configuration, with which the quantized excitations of the atomic nuclei, namely phonons, can be investigated separately from the electrons [2]. It is important to note, however, that the BOA does not separate the electronic and atomic degrees of freedom completely, and a remaining coupling term can cause transitions between the eigenstates of the electron and phonon systems [3]. This electronphonon interaction (EPI) problem was first studied by Bloch [4], and later understood as the main source of resistance to electrical conduction in metals and semiconductors at higher temperatures [3,5,6], and played the key role in the microscopic theory of superconductivity [7].While the effect of the EPI on electron transport has been widely studied in great detail and has become standard content in textbooks [3,5,6], its effect on phonon transport has received much less attention. In our opinion the reason is twofold. First of all, the carrier concentration in semiconductors for conventional microelectronic and optoelectronic applications is typically below 10 19 cm −3 [8], and as we shall show later, the impact of the EPI on phonon transport in this concentration range turns out to be too small to invoke any practical interest. On the other hand, in metals with typical carrier concentrations greater than 10 22 cm −3 , the thermal conduction is dominated by electrons, an...

The monolayer of black phosphorous, or "phosphorene", has recently emerged as a new 2D semiconductor with intriguing highly anisotropic transport properties. Existing calculations of its intrinsic phonon-limited electronic transport properties so far rely on the deformation potential approximation, which is in general not directly applicable to anisotropic materials since the deformation along one specific direction can scatter electrons traveling in all directions. We perform a first-principles calculation of the electron-phonon interaction in phosphorene based on density functional perturbation theory and Wannier interpolation.Our calculation reveals that 1) the high anisotropy provides extra phase space for electronphonon scattering, and 2) optical phonons have appreciable contributions. Both effects cannot be captured by the deformation potential calculations. Our simulation predicts carrier mobilities ~170 cm 2 /Vs for both electrons and holes at 300K, and a thermoelectric figure of merit zT of up to 0.14 in p-type impurity-free phosphorene at 500K.

We show that thermal rectification (TR) in asymmetric graphene nanoribbons (GNRs) is originated from phonon confinement in the lateral dimension, which is a fundamentally new mechanism different from that in macroscopic heterojunctions. Our molecular dynamics simulations reveal that, though TR is significant in nanosized asymmetric GNRs, it diminishes at larger width. By solving the heat diffusion equation, we prove that TR is indeed absent in both the total heat transfer rate and local heat flux for bulk-size asymmetric single materials, regardless of the device geometry or the anisotropy of the thermal conductivity. For a deeper understanding of why lateral confinement is needed, we have performed phonon spectra analysis and shown that phonon lateral confinement can enable three possible mechanisms for TR: phonon spectra overlap, inseparable dependence of thermal conductivity on temperature and space, and phonon edge localization, which are essentially related to each other in a complicated manner. Under such guidance, we demonstrate that other asymmetric nanostructures, such as asymmetric nanowires, thin films, and quantum dots, of a single material are potentially high-performance thermal rectifiers. KEYWORDS: Thermal rectification, phonon lateral confinement, phonon localization, edge/surface effect, molecular dynamics, phonon spectra I nspired by the impact of electric diodes on the electronics industry, extensive attention has been given to the search of rectification of various other transport processes.1−3 Thermal rectification (TR) is a diode-like behavior where the heat current changes in magnitude when the applied temperature (T) bias is reversed in direction. A perfect thermal rectifier would be one that is highly thermal conductive in one direction while insulating in the other, and it is expected to work as a promising thermal management component of electronics as chip size continues decreasing or as a stand-alone thermally driven computing system replacing the electronic ones in certain conditions.Numerous studies have predicted or demonstrated the existence of TR in bulk or nanosized systems, most of which are heterojunctions (HJ) or graded systems.3−11 For twosegment systems, TR was usually attributed to the different Tdependence of the thermal conductivity (κ), 5,7 and for interfaces TR has been interpreted as the different phonon spectra mismatch before and after reversing the applied T bias. Phonon localization was suggested to play a role as well. 12,13 Recently, TR was also predicted to occur in asymmetric pristine carbon nanostructures, 13−17 which are composed of a single material and are attractive for their simple structure and high thermal conductance. 18 However, the origin of TR in such homogeneous nanostructures remains unclear. In this work, we have observed, using molecular dynamics and analytical derivations, that phonon confinement in the lateral dimension is required for TR to occur in asymmetric homogeneous structures made of a single material. We further show that...

SummaryLipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids.

We perform molecular dynamics (MD) simulations with phonon spectral analysis aiming at understanding the two dimensional (2D) thermal transport in suspended and supported graphene. Within the framework of equilibrium MD simulations, we perform spectral energy density (SED) analysis to obtain the lifetime of individual phonon modes. The per-mode contribution to thermal conductivity is then calculated to obtain the lattice thermal conductivity in the temperature range 300-650 K. In contrast to prior studies, our results suggest that the contribution from out-of-plane acoustic (or ZA) branch to thermal conductivity is around 25-30% in suspended single-layer graphene (SLG) at room temperature. The thermal conductivity is found to reduce when SLG is put on amorphous SiO2 substrate. Such reduction is attributed to the strengthened scattering in all phonon modes in the presence of the substrate. Among them, ZA modes are mostly affected with their contribution to thermal conductivity reduced to around 15%. As a result, thermal transport is dominated by in-plane acoustic phonon modes in supported SLG.