Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.
Differences in genetic background in model organisms can have complex effects on phenotypes of interest. We previously reported a difference in hermaphrodite lifespan between two wild-type lines widely used by C. elegans researchers (N2 hermaphrodite and male stocks). Here, using pathology-based approaches and genome sequencing, we identify the cause of this difference as a nonsense mutation in the filamin gene fln-2 in the male stock, which reduces early mortality caused by pharyngeal infection. We show how fln-2 variation explains previous discrepancies involving effects of sir-2.1 (sirtuin deacetylase) on ageing, and show that in a fln-2(+) background, sir-2.1 over-expression causes an FUDR (DNA synthesis inhibitor)-dependent reduction in pharyngeal infection and increase in lifespan. In addition we show how fln-2 variation confounds effects on lifespan of daf-2 (insulin/IGF-1 signalling), daf-12 (steroid hormone signalling), and eat-2 (putative dietary restriction). These findings underscore the importance of identifying and controlling genetic background variation.
Seawater is one of the most abundant natural resources on our planet. Electrolysis of seawater is not only a promising approach to produce clean hydrogen energy, but also of great significance to seawater desalination. The implementation of seawater electrolysis requires robust and efficient electrocatalysts that can sustain seawater splitting without chloride corrosion, especially for the anode. Here we report a three-dimensional core-shell metal-nitride catalyst consisting of NiFeN nanoparticles uniformly decorated on NiMoN nanorods supported on Ni foam, which serves as an eminently active and durable oxygen evolution reaction catalyst for alkaline seawater electrolysis. Combined with an efficient hydrogen evolution reaction catalyst of NiMoN nanorods, we have achieved the industrially required current densities of 500 and 1000 mA cm(-2) at record low voltages of 1.608 and 1.709 V, respectively, for overall alkaline seawater splitting at 60 degrees C. This discovery significantly advances the development of seawater electrolysis for large-scale hydrogen production.
High strength and high ductility are often mutually exclusive properties for structural metallic materials. This is particularly important for aluminum (Al)-based alloys which are widely commercially employed. Here, we introduce a hierarchical nanostructured Al alloy with a structure of Al nanograins surrounded by nano-sized metallic glass (MG) shells. It achieves an ultrahigh yield strength of 1.2 GPa in tension (1.7 GPa in compression) along with 15% plasticity in tension (over 70% in compression). The nano-sized MG phase facilitates such ultrahigh strength by impeding dislocation gliding from one nanograin to another, while continuous generation-movement-annihilation of dislocations in the Al nanograins and the flow behavior of the nano-sized MG phase result in increased plasticity. This plastic deformation mechanism is also an efficient way to decrease grain size to sub-10 nm size for low melting temperature metals like Al, making this structural design one solution to the strength-plasticity trade-off.
Great efforts have been made in the activation of a C(alkenyl)-H bond vicinal to the directing group to proceed via five- or six-membered endo-metallocycles. In stark contrast, functionalization of a C(alkenyl)-H bond geminal to the directing group via exo-metallocycle pathway continued to be elusive. Here we report the selective transformation of an olefinic C-H bond that is geminal to the directing group bearing valuable hydroxyl, carbamate or amide into a C-C bond, which proceeds through four- to eight-membered exo-palladacycles. Compared to the reported mechanisms proceeding only through six-membered exo-palladacycles via N,N-bidentate chelation, our weak and O-monodentate chelation-assisted C (alkenyl)-H activations tolerate longer or shorter distances between the olefinic C-H bonds and the coordinating groups, allowing for the functionalizations of many olefinic C-H bonds in alkenyl alcohols, carbamates and amides. The synthetic applicability has been demonstrated by the preparative scale and late-stage C-H functionalization of steroid and ricinoleate derivatives.
Electromodulation (EM) spectroscopy, a powerful technique to monitor the changes in polarizability p and dipole moment u of materials upon photo-excitation, can bring direct insight into the excitonic properties of materials. However, extracting Delta p and Delta u from the electromodulation spectrum relies on fitting with optical absorption of the materials where optical effect in different device geometries might introduce large variation in the extracted values. Here, we demonstrate a systematic electromodulation study with various fitting approaches in both commonly adopted reflection and transmission device architectures. Strikingly, we have found that the previously ascribed continuum state threshold from the deviation between the measured and fitting results is questionable. Such deviation is found to be caused by the overlooked optical interference and electrorefraction effect. A generalized electromodulation model is proposed to incorporate the two effects, and the extracted Delta p and Delta u have excellent consistency in both reflection and transmission modes in all organic film thicknesses.
Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by (UC)-C-13 glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.
Mantle melts provide a window on processes related to global plate tectonics. The composition of chromian spinel (Cr-spinel) from mafic-ultramafic rocks has been widely used for tracing the geotectonic environments, the degree of mantle melting and the rate of midocean ridge spreading. The assumption is that Cr-spinel's core composition (Cr# = Cr/(Cr + Al)) is homogenous, insensitive to post-formation modification and therefore a robust petrogenetic indicator. However, we demonstrate that the composition of Cr-spinel can be modified by fluid/melt-rock interactions in both sub-arc and sub-mid oceanic mantle. Metasomatism can produce Al-Cr heterogeneity in Cr-spinel that lowers the Cr/Al ratio, and therefore modifies the Cr#, making Cr# ineffective as a geotectonic and mantle melting indicator. Our analysis also demonstrates that Cr-spinel is a potential sink for fluid-mobile elements, especially in subduction zone environments. The heterogeneity of Cr# in Cr-spinel can, therefore, be used as an excellent tracer for metasomatic processes.
The modification of soil organic matter (SOM) decomposition by plant carbon (C) input (priming effect) represents a critical biogeochemical process that controls soil C dynamics. However, the patterns and drivers of the priming effect remain hidden, especially over broad geographic scales under various climate and soil conditions. By combining systematic field and laboratory analyses based on multiple analytical and statistical approaches, we explore the determinants of priming intensity along a 2200 km grassland transect on the Tibetan Plateau. Our results show that SOM stability characterized by chemical recalcitrance and physico-chemical protection explains more variance in the priming effect than plant, soil and microbial properties. High priming intensity (up to 137% of basal respiration) is associated with complex SOM chemical structures and low mineral-organic associations. The dependence of priming effect on SOM stabilization mechanisms should be considered in Earth System Models to accurately predict soil C dynamics under changing environments.
The integration of luminescence and chirality in easy-scalable metal-organic frameworks gives rise to the development of advanced luminescent sensors. To date, the synthesis of chiral metal-organic frameworks is poorly predictable and their chirality primarily originates from components that constitute the frameworks. By contrast, the introduction of chirality into the pores of metal-organic frameworks has not been explored to the best of our knowledge. Here, we demonstrate that chirality can be introduced into an anionic Zn-based metal-organic framework via simple cation exchange, yielding dual luminescent centers comprised of the ligand and Tb3+ ions, accompanied by a chiral center in the pores. This bifunctional material shows enantioselectivity luminescent sensing for a mixture of stereoisomers, demonstrated for Cinchonine and Cinchonidine epimers and amino alcohol enantiomers, from which the quantitative determination of the stereoisomeric excess has been obtained. This study paves a pathway for the design of multifunctional metal-organic framework systems as a useful method for rapid sensing of chiral molecules.
Majorana zero modes are localized quasiparticles that obey non-Abelian exchange statistics. Braiding Majorana zero modes forms the basis of topologically protected quantum operations which could, in principle, significantly reduce qubit decoherence and gate control errors at the device level. Therefore, searching for Majorana zero modes in various solid state systems is a major topic in condensed matter physics and quantum computer science. Since the first experimental signature observed in hybrid superconductor-semiconductor nanowire devices, this field has witnessed a dramatic expansion in material science, transport experiments and theory. While making the first topological qubit based on these Majorana nanowires is currently an ongoing effort, several related important transport experiments are still being pursued in the near term. These will not only serve as intermediate steps but also show Majorana physics in a more fundamental aspect. In this perspective, we summarize these key Majorana experiments and the potential challenges.
Optical vector analysis (OVA) capable of achieving magnitude and phase responses is essential for the fabrication and application of emerging optical devices. Conventional OVA often has to make compromises among resolution, dynamic range, and bandwidth. Here we show an original method to meet the measurement requirements for ultra-wide bandwidth, ultra-high resolution, and ultra-large dynamic range simultaneously, based on an asymmetric optical probe signal generator (ASG) and receiver (ASR). The ASG and ASR remove the measurement errors introduced by the modulation nonlinearity and enable an ultra-large dynamic range. Thanks to the wavelength-independence of the ASG and ASR, the measurement range can increase by 2 N times by applying an N-tone optical frequency comb without complicated operation. In an experiment, OVA with a resolution of 334 Hz (2.67 attometer in the 1550-nm band), a dynamic range of > 90 dB and a measurement range of 1.075 THz is demonstrated.
The Dresselhaus and Rashba effects are well-known phenomena in solid-state physics, in which spin-orbit coupling splits spin-up and spin-down energy bands of nonmagnetic non-centrosymmetric crystals. Here, we discuss a phenomenon we dub band splitting with vanishing spin polarizations (BSVSP), in which, as usual, spin-orbit coupling splits the energy bands in nonmagnetic non-centrosymmetric systems. Surprisingly, however, both split bands show no net spin polarization along certain high-symmetry lines in the Brillouin zone. In order to rationalize this phenomenon, we propose a classification of point groups into pseudo-polar and non-pseudo-polar groups. By means of first-principles simulations, we demonstrate that BSVSP can take place in both symmorphic (e.g., bulk GaAs) and non-symmorphic systems (e.g., two dimensional ferroelectric SnTe). Furthermore, we identify a linear magnetoelectric coupling in reciprocal space, which could be employed to tune the spin polarization with an external electric field. The BSVSP effect and its manipulation could therefore form the basis for future spintronic devices.
The botanical family Cucurbitaceae includes a variety of fruit crops with global or local economic importance. How their genomes evolve and the genetic basis of diversity remain largely unexplored. In this study, we sequence the genome of the wax gourd (Benincasa hispida), which bears giant fruit up to 80 cm in length and weighing over 20 kg. Comparative analyses of six cucurbit genomes reveal that the wax gourd genome represents the most ancestral karyotype, with the predicted ancestral genome having 15 proto-chromosomes. We also resequence 146 lines of diverse germplasm and build a variation map consisting of 16 million variations. Combining population genetics and linkage mapping, we identify a number of regions/genes potentially selected during domestication and improvement, some of which likely contribute to the large fruit size in wax gourds. Our analyses of these data help to understand genome evolution and function in cucurbits.