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Resistance to the selective estrogen receptor modulator tamoxifen and to aromatase inhibitors that lower circulating estradiol occurs in up to 50% of patients, generally leading to an endocrine-independent ER+ phenotype. Selective ER downregulators (SERDs) are able to ablate ER and thus, theoretically, to prevent survival of both endocrine-dependent and -independent ER+ tumors. The clinical SERD fulvestrant is hampered by intramuscular administration and undesirable pharmacokinetics. Novel SERDs were designed using the 6-OH-benzothiophene (BT) scaffold common to arzoxifene and raloxifene. Treatment-resistant (TR) ER+ cell lines (MCF-7:5C and MCF-7:TAM1) were used for optimization, followed by validation in the parent endocrine-dependent cell line (MCF-7:WS8), in 2D and 3D cultures, using ERα in-cell westerns, ERE-luciferase, and cell viability assays, with 2 (GDC-0810/ARN-810) used for comparison. Two BT SERDs with superior in vitro activity to 2 were studied for bioavailability and shown to cause regression of a TR, endocrine-independent ER+ xenograft superior to that with 2. [ABSTRACT FROM AUTHOR]

Dislocations are one-dimensional line defects in three-dimensional crystals or periodic structures. It is common that the dislocation networks made of interactive dislocations be generated during plastic deformation. In van der Waals layered materials, the highly anisotropic nature facilitates the formation of such dislocation networks, which is critical for the friction or exfoliation behavior for these materials. By transmission electron microscopy analysis, we found the topological defects in such dislocation networks can be perfectly rationalized in the framework of traditional dislocation theory, which we applied the name "hyperdislocations". Due to the strong pinning effect of hyperdislocations, the state of exfoliation can be easily triggered by 1° twisting between two layers, which also explains the origin of disregistry and frictionlessness for all of the superlubricants that are widely used for friction reduction and wear protection. [ABSTRACT FROM AUTHOR]

One well-known argument about a one-dimensional (1D) system is that 1D phase transition at finite temperature cannot exist even though this concept depends on conditions such as range of interaction, external fields, and periodicity. Therefore, 1D systems usually have random fluctuations with intrinsic domain walls arising that naturally bring disorder during transition. Herein, we introduce a real 1D system in which artificially created defects can induce a well-defined 1D phase transition. The dynamics of structural reconstructions at graphene zigzag edges are examined by in situ aberration-corrected transmission electron microscopy. Combined with an in-depth analysis by ab initio simulations and quantum chemical molecular dynamics, the complete defect induced 1D phase transition dynamics at graphene zigzag edge is clearly demonstrated and understood on the atomic scale. Further, following this phase transition scheme, graphene nanoribbons (GNR) with different edge symmetries can be fabricated and, according to our electronic structure and quantum transport calculations, a metal-insulator-semiconductor transition for ultrathin GNRs is proposed. [ABSTRACT FROM AUTHOR]

Single-atom catalysts are of great interest because of their high efficiency. In the case of chemically deposited sp2 carbon, the implementation of a single transition metal atom for growth can provide crucial insight into the formation mechanisms of graphene and carbon nanotubes. This knowledge is particularly important if we are to overcome fabrication difficulties in these materials and fully take advantage of their distinct band structures and physical properties. In this work, we present atomically resolved transmission EM in situ investigations of single Fe atoms at graphene edges. Our in situ observations show individual iron atoms diffusing along an edge either removing or adding carbon atoms (viz., catalytic action). The experimental observations of the catalytic behavior of a single Fe atom are in excellent agreement with supporting theoretical studies. In addition, the kinetics of Fe atoms at graphene edges are shown to exhibit anomalous diffusion, which again, is in agreement with our theoretical investigations. [ABSTRACT FROM AUTHOR]

The article presents research into free-standing two-dimensional (2D) metal formation, focusing on the creation of a free-standing crystalline atomically thin layer of iron (Fe). Topic include the use of low-voltage spherical aberration corrected transmission electron microscopy (LVACTEM), the enhanced magnetic properties of single-atom-thick 2D Fe membranes, and potential of the results in the formation of graphene membrane 2D structures.

Instantaneous electrical breakdown measurements of GaN and Ag nanowires are performed by an in situ transmission electron microscopy method. Our results directly reveal the mechanism that typical thermally heated semiconductor nanowires break at the midpoint, while metallic nanowires breakdown near the two ends due to the stress induced by electromigration. The different breakdown mechanisms for the nanowires are caused by the different thermal and electrical properties of the materials. [ABSTRACT FROM AUTHOR]

The mass transportation mechanism in electric-biased carbon nanotubes (CNTs) is investigated experimentally. Except for the widely accepted electromigration mechanism, we find out the thermal effect can also induce the mass transportation in the form of thermomigration or thermal evaporation. Moreover, the convincing in situ transmission electron microscope experiment results show the thermal gradient force overrides the electromigration force in most conditions, according to specific parameters of the CNTs and “cargos”. A full analysis on the thermal gradient force and electromigration force imposed on the cargos is given, thus our experimental results are well explained and understood. [ABSTRACT FROM AUTHOR]

Deals with the characterization of the Aspergillus nidulans septin gene family. Functions of the septin gene family; Orthologous classes where septin genes belong; Grouping of fungal septins in phylogenetic analysis.

We report the observation of an electric field in twisted-bilayer molybdenum disulfide (MoS2) and elucidate its correlation with local polar domains using four-dimensional scanning transmission electron microscopy (4D-STEM) and first-principles calculations. We reveal the emergence of in-plane topological vortices within the periodic moiré patterns for both commensurate structures at small twist angles and the incommensurate quasicrystal structure that occurs at a 30° twist. The large-angle twist leads to mosaic chiral vortex patterns with tunable characteristics. A twisted quasicrystal bilayer, characterized by its 12-fold rotational symmetry, hosts complex vortex patterns and can be manipulated by picometer-scale interlayer displacement. Our findings highlight that twisting 2D bilayers is a versatile strategy for tailoring local electric polar vortices. [ABSTRACT FROM AUTHOR]

Synthetic lethality is a potential strategy for cancer treatment by specifically promoting the death of cancer cells with particular defects such as the loss of the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB and TSC2 induces synergistic apoptosis during the development of Drosophila melanogaster and in cancer cells. However, the in vivo mechanism of this syntheticlethal interaction is not clear. Here, we show that synergistic cell death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/ gig, respectively, or overexpress Rheb and dE2F1, are correlated with synergistic defects in G1-S control, which causes cells to accumulate DNA damage. Coexpression of the G1-S inhibitor Dap, but not the G2-M inhibitor dWee1, decreases DNA damage and reduces cell death. In addition, we show that rbf and dtsc1 mutant cells are under energy stress, are sensitive to decreased energy levels and depend on the cellular energy stress-response pathway for survival. Decreasing mitochondrial ATP synthesis by inactivating cova or abrogating the energy-stress response by removing the metabolic regulator LKB1 both enhance the elimination of cells lacking either rbf or dtsc1. These observations, in conjunction with the finding that deregulation of TORC1 induces activation of JNK, indicate that multiple cellular stresses are induced and contribute to the synthetic-lethal interactions between RB and TSC1/TSC2 inactivation. The insights gained from this study suggest new approaches for targeting RB-deficient cancers. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRASinduced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition. [ABSTRACT FROM AUTHOR]

The article focuses on the study of the Anomalous fracture in two-dimensional rhenium disulfide. Topics disicussed include low-dimensional materials usually exhibit mechanical properties from those of their bulk counterparts; and studies provide critical insights into the atomistic processes of fracture and unveil the origin of the brittleness in the 2D materials.

Almost 70% of breast cancers are estrogen receptor a (ERa) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERa such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERa would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth. [ABSTRACT FROM AUTHOR]

Artificial van der Waals heterostructures with two-dimensional (2D) atomic crystals are promising as an active channel or as a buffer contact layer for next-generation devices. However, genuine 2D heterostructure devices remain limited because of impurity-involved transfer process and metastable and inhomogeneous heterostructure formation. We used laser-induced phase patterning, a polymorph engineering, to fabricate an ohmic heterophase homojunction between semiconducting hexagonal (2H) and metallic monoclinic (1T') molybdenum ditelluride (MoTe2) that is stable up to 300°C and increases the carrier mobility of the MoTe2 transistor by a factor of about 50, while retaining a high on/off current ratio of 106. In situ scanning transmission electron microscopy results combined with theoretical calculations reveal that the Te vacancy triggers the local phase transition in MoTe2, achieving a true 2D device with an ohmic contact. [ABSTRACT FROM AUTHOR]

The formation, propagation, and structure of nanoscale cracks determine the failure mechanics of engineered materials. Herein, we have captured, with atomic resolution and in real time, unit cell-by-unit cell lattice-trapped cracking in two-dimensional (2D) rhenium disulfide (ReS2) using in situ aberration corrected scanning transmission electron microscopy (STEM). Our real time observations of atomic configurations and corresponding strain fields in propagating cracks directly reveal the atomistic fracture mechanisms. The entirely brittle fracture with non-blunted crack tips as well as perfect healing of cracks have been observed. The mode I fracture toughness of 2D ReS2 is measured. Our experiments have bridged the linear elastic deformation zone and the ultimate nm-sized nonlinear deformation zone inside the crack tip. The dynamics of fracture has been explained by the atomic lattice trapping model. The direct visualization on the strain field in the ongoing crack tips and the gained insights of discrete bond breaking or healing in cracks will facilitate deeper insights into how atoms are able to withstand exceptionally large strains at the crack tips. [ABSTRACT FROM AUTHOR]

Synthesis of monolayer transition metal dichalcogenides (TMDs) via chemical vapor deposition relies on several factors such as precursor, promoter, substrate, and surface treatment of substrate. Among them, the use of promoter is crucial for obtaining uniform and large-area monolayer TMDs. Although promoters have been speculated to enhance adhesion of precursors to the substrate, their precise role in the growth mechanism has rarely been discussed. Here, we report the role of alkali metal promoter in growing monolayer TMDs. The growth occurred via the formation of sodium metal oxides which prevent the evaporation of metal precursor. Furthermore, the silicon oxide substrate helped to decrease the Gibbs free energy by forming sodium silicon oxide compounds. The resulting sodium metal oxide was anchored within such concavities created by corrosion of silicon oxide. Consequently, the wettability of the precursors to silicon oxide was improved, leading to enhance lateral growth of monolayer TMDs. [ABSTRACT FROM AUTHOR]