Seventy percent of breast cancers express estrogen receptor (ER) and most of these are sensitive to ER inhibition. However, many such tumors become refractory to inhibition of estrogen action in the metastatic setting for unknown reasons. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER+ breast tumors and identified mutations in the ligand binding domain (LBD) of ESR1 in 14/80 cases. These included highly recurrent mutations p.Tyr537Ser/Asn and p.Asp538Gly. Molecular dynamics simulations suggest the Tyr537Ser and Asp538Gly structures lead to hydrogen bonding of the mutant amino acid with Asp351, thus favoring the receptor’s agonist conformation. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may have significant therapeutic benefit.

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Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Monolayer transition metal dichalcogenide (TMDC) crystals, as direct-gap materials with unusually strong light-matter interaction, have attracted much recent attention. In contrast to the initial understanding, the minima of the conduction band are predicted to be spin split. Because of this splitting and the spin-polarized character of the valence bands, the lowest-lying excitonic states in WX 2 (X=S, Se) are expected to be spin-forbidden and optically dark. To date, however, there has been no direct experimental probe of these dark band-edge excitons, which strongly influence the light emission properties of the material. Here we show how an in-plane magnetic field can brighten the dark excitonic states and allow their properties to be revealed experimentally in monolayer WSe 2 . In particular, precise energy levels for both the neutral and charged dark excitons were obtained and compared with ab-initio calculations using the GW-BSE approach. Greatly increased emission and valley lifetimes were observed for the brightened dark states as a result of their spin configuration. These studies directly probe the excitonic spin manifold and provide a new route to tune the optical and valley properties of these prototypical twodimensional semiconductors.The electronic and optical properties of ultrathin TMDC crystals in the MX 2 (M = Mo, W, X = S, Se) family have attracted much recent attention. These 2D semiconductors exhibit a direct bandgap at monolayer thickness 1, 2 , have strong and anomalous excitonic interactions [3][4][5] , and offer the potential for highly efficient light emission. The materials also provide an ideal platform for access to the valley degree of freedom, since the optical selection rules provide a

A striking feature of bilayer graphene is the induction of a significant band gap in the electronic states by the application of a perpendicular electric field [1][2][3][4][5][6][7] . Thicker graphene layers are also highly attractive materials. The ability to produce a band gap in these systems is of great fundamental and practical interest. Both experimental 8 and theoretical [9][10][11][12][13][14][15][16] investigations of graphene trilayers with the typical ABA layer stacking have, however, revealed the lack of any appreciable induced gap. Here we contrast this behaviour with that exhibited by graphene trilayers with ABC crystallographic stacking. The symmetry of this structure is similar to that of AB-stacked graphene bilayers and, as shown by infrared conductivity measurements, permits a large band gap to be formed by an applied electric field. Our results demonstrate the critical and hitherto neglected role of the crystallographic stacking sequence on the induction of a band gap in few-layer graphene.Producing a controlled and tunable band gap in graphene is a topic of central importance [1][2][3][4][5][6][7]17,18 . In addition to the intrinsic interest of altering the electronic properties of materials, the availability of an adjustable band gap opens up the possibility of a much wider range of applications for graphene in electronics and photonics. Both single-and few-layer graphene in their unperturbed state lack a band gap 19,20 . However, few-layer graphene materials under the application of a symmetry-lowering perpendicular electric field may exhibit an induced gap [9][10][11][12][13][14][15][16]21,22 . In this regard, trilayer graphene is an attractive material system. Unlike bilayer graphene, however, trilayers, which typically exhibit Bernal (ABA) stacking order and the associated mirror symmetry (Fig. 1a), have been shown both theoretically 9-16 and experimentally 8 not to support the induction of a significant band gap when subjected to a perpendicular electric field. As discussed below, this behaviour follows from the mirror symmetry of the unperturbed ABA trilayer 10,23 . Recent research 24,25 has, however, reported the existence of a new type of trilayer graphene, one with ABC (rhombohedral) stacking order between the graphene sheets (Fig. 1b). This crystal structure, like that of the bilayer, possesses inversion symmetry, but lacks mirror symmetry (Fig. 1b). The low-energy electronic structure of the ABC trilayer 20,22 is accordingly more similar to that of the AB-stacked bilayer graphene. In particular, the undoped ABC trilayer has only two-fold degeneracy 20 at the Fermi energy, like the graphene bilayer, rather than the four-fold degeneracy found in the ABA trilayer 20,23 . The two-fold degeneracy in the ABC trilayer band structure can be readily lifted by imposing different potentials on the top and bottom graphene layers by an applied electric field, which leads to the opening of a band gap 9,10,[13][14][15][16]21,22 . Although theory has predicted the induction of a large band gap fo...

Antimony selenide (Sb2Se3) has a one-dimensional (1D) crystal structure comprising of covalently bonded (Sb4Se6)n ribbons stacking together through van der Waals force. This special structure results in anisotropic optical and electrical properties. Currently, the photovoltaic device performance is dominated by the grain orientation in the Sb2Se3 thin film absorbers. Effective approaches to enhance the carrier collection and overall power-conversion efficiency are urgently required. Here, we report the construction of Sb2Se3 solar cells with high-quality Sb2Se3 nanorod arrays absorber along the [001] direction, which is beneficial for sun-light absorption and charge carrier extraction. An efficiency of 9.2%, which is the highest value reported so far for this type of solar cells, is achieved by junction interface engineering. Our cell design provides an approach to further improve the efficiency of Sb2Se3-based solar cells.