Histone acetylation is important in chromatin remodelling and gene activation. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are approximately 110-amino-acid modules found in many chromatin-associated proteins. Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy. The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated. Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

Direct interactions of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) with inwardly rectifying potassium channels are stronger with channels rendered constitutively active by binding to PtdIns(4,5)P2, such as IRK1, than with G-protein-gated channels (GIRKs). As a result, PtdIns(4,5)P2 alone can activate IRK1 but not GIRKs, which require extra gating molecules such as the beta gamma subunits of G proteins or sodium ions. Here we identify two conserved residues near the inner-membrane interface of these channels that are critical in interactions with PtdIns(4,5)P2. Between these two arginines, a conservative change of isoleucine residue 229 in GIRK4 to the corresponding leucine found in IRK1 strengthens GIRK4-PtdIns(4,5)P2 interactions, eliminating the need for extra gating molecules. A negatively charged GIRK4 residue, two positions away from the most strongly interacting arginine, mediates stimulation of channel activity by sodium by strengthening channel-PtdIns(4,5)P2 interactions. Our results provide a mechanistic framework for understanding how distinct gating mechanisms of inwardly rectifying potassium channels allow these channels to subserve their physiological roles.

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Nonreciprocal wave propagation typically requires strong nonlinear materials to break time reversal symmetry. Here, we utilized a sonic-crystal-based acoustic diode that had broken spatial inversion symmetry and experimentally realized sound unidirectional transmission in this acoustic diode. These novel phenomena are attributed to different mode transitions as well as their associated different energy conversion efficiencies among different diffraction orders at two sides of the diode. This nonreciprocal sound transmission could be systematically controlled by simply mechanically rotating the square rods of the sonic crystal. Different from nonreciprocity due to the nonlinear acoustic effect and broken time reversal symmetry, this new model leads to a one-way effect with higher efficiency, broader bandwidth, and much less power consumption, showing promising applications in various sound devices. DOI: 10.1103/PhysRevLett.106.084301 PACS numbers: 43.35.+d, 42.79.Dj, 43.25.+y Electrical diodes, due to their capability of rectification of current flux, have significantly revolutionized fundamental science and advanced technology in various aspects of our routine life. Motivated by this one-way effect of electric currents, considerable effort has been dedicated to the study of the unidirectional nonreciprocal transmission of electromagnetic waves, showing important promise in optical and rf communications [1][2][3][4][5][6]. The realization of such nonreciprocal and unidirectional propagation requires either a broken time reversal symmetry [1-4] or a broken spatial inversion symmetry [5,6] in the artificial photonic structures (e.g., photonic crystals).Sonic crystals (SCs), in an analogy with the electronic and photonic band structures of semiconductors and photonic crystals, have shown promising impacts in acoustic devices and applications that can efficiently trap, guide, and manipulate sound [7][8][9][10][11][12][13][14][15]. In the past two decades, with rapid developments in SCs ranging from engineering of band structure for bulk acoustic waves to design of acoustic grating for surface waves, a series of fascinating acoustic effects are consequently demonstrated, such as acoustic band gaps [8,9], negative refractions [10][11][12][13][14], and extraordinary transmission [15]. It is therefore expected, with a sophisticated SC design, that the exotic properties of SCs can lead to more counterintuitive sound manipulation, for example, the realization of acoustic diodes that can break down the conventional transmission reciprocity [16][17][18][19]. Similar to electromagnetic wave, sound usually propagates reciprocally back and forth along a given path. Unidirectional flux transmission requires considering the breaking of parity and time symmetry simultaneously in uniform media [20] that do not typically exist in nature. Therefore, SCs are currently considered good candidates to implement nonreciprocal and unidirectional sound propagation. The previous studies proposed the utilization of acoustic nonlinear effec...