In a calcium-dependent interaction critical for blood coagulation, vitamin K-dependent blood coagulation proteins bind cell membranes containing phosphatidylserine via gamma-carboxyglutamic acid-rich (Gla) domains. Gla domain-mediated protein-membrane interaction is required for generation of thrombin, the terminal enzyme in the coagulation cascade, on a physiologic time scale. We determined by X-ray crystallography and NMR spectroscopy the lysophosphatidylserine-binding site in the bovine prothrombin Gla domain. The serine head group binds Gla domain-bound calcium ions and Gla residues 17 and 21, fixed elements of the Gla domain fold, predicting the structural basis for phosphatidylserine specificity among Gla domains. Gla domains provide a unique mechanism for protein-phospholipid membrane interaction. Increasingly Gla domains are being identified in proteins unrelated to blood coagulation. Thus, this membrane-binding mechanism may be important in other physiologic processes.

Genome rearrangements are important in evolution, cancer, and other diseases. Precise mapping of the rearrangements is essential for identification of the involved genes, and many techniques have been developed for this purpose. We show here that end-sequence profiling (ESP) is particularly well suited to this purpose. ESP is accomplished by constructing a bacterial artificial chromosome (BAC) library from a test genome, measuring BAC end sequences, and mapping end-sequence pairs onto the normal genome sequence. Plots of BAC end-sequences density identify copy number abnormalities at high resolution. BACs spanning structural aberrations have end pairs that map abnormally far apart on the normal genome sequence. These pairs can then be sequenced to determine the involved genes and breakpoint sequences. ESP analysis of the breast cancer cell line MCF-7 demonstrated its utility for analysis of complex genomes. End sequencing of Ϸ8,000 clones (0.37-fold haploid genome clonal coverage) produced a comprehensive genome copy number map of the MCF-7 genome at better than 300-kb resolution and identified 381 genome breakpoints, a subset of which was verified by fluorescence in situ hybridization mapping and sequencing.

Low-loss photonic integrated circuits and microresonators have enabled a wide range of applications, such as narrow-linewidth lasers and chip-scale frequency combs. To translate these into a widespread technology, attaining ultralow optical losses with established foundry manufacturing is critical. Recent advances in integrated Si3N4 photonics have shown that ultralow-loss, dispersion-engineered microresonators with quality factors Q > 10 × 106 can be attained at die-level throughput. Yet, current fabrication techniques do not have sufficiently high yield and performance for existing and emerging applications, such as integrated travelling-wave parametric amplifiers that require meter-long photonic circuits. Here we demonstrate a fabrication technology that meets all requirements on wafer-level yield, performance and length scale. Photonic microresonators with a mean Q factor exceeding 30 × 106, corresponding to 1.0 dB m−1 optical loss, are obtained over full 4-inch wafers, as determined from a statistical analysis of tens of thousands of optical resonances, and confirmed via cavity ringdown with 19 ns photon storage time. The process operates over large areas with high yield, enabling 1-meter-long spiral waveguides with 2.4 dB m−1 loss in dies of only 5 × 5 mm2 size. Using a response measurement self-calibrated via the Kerr nonlinearity, we reveal that the intrinsic absorption-limited Q factor of our Si3N4 microresonators can exceed 2 × 108. This absorption loss is sufficiently low such that the Kerr nonlinearity dominates the microresonator’s response even in the audio frequency band. Transferring this Si3N4 technology to commercial foundries can significantly improve the performance and capabilities of integrated photonics.

The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers. SIGNIFICANCE This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.