Abstract: The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in the demand for inhibitory anti-CRISPR molecules. Current small-molecule inhibitor discovery platforms are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity, and require high concentration of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Herein, Applicants report a high-throughput discovery pipeline consisting of a FRET-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentration, and targets all catalytic steps. Applicants applied this pipeline to identify BRD7586, a cell-permeable small-molecule inhibitor of SpCas9, that is 2-fold more potent than current inhibitors. Furthermore, unlike the reported inhibitors, BRD7586 enhanced SpCas9 specificity and its activity was independent of the genomic loci, DNA repair pathway, or mode of nuclease delivery.

Abstract: The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, —C(?NR?)—NR?R? or —CH2—CH?CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.

Abstract: A semiconductor device package includes a substrate, a silicon (Si) or silicon carbide (SiC) semiconductor die, and a metal layer on a surface of the semiconductor die. The metal layer includes a bonding surface that is attached to a surface of the substrate by a die attach material. The bonding surface includes opposing edges that extend along a perimeter of the semiconductor die, and one or more non-orthogonal corners that are configured to reduce stress at an interface between the bonding surface and the die attach material. Related devices and fabrication methods are also discussed.

Abstract: A semiconductor device package includes a substrate, a silicon (Si) or silicon carbide (SiC) semiconductor die, and a metal layer on a surface of the semiconductor die. The metal layer includes a bonding surface that is attached to a surface of the substrate by a die attach material. The bonding surface includes opposing edges that extend along a perimeter of the semiconductor die, and one or more non-orthogonal corners that are configured to reduce stress at an interface between the bonding surface and the die attach material. Related devices and fabrication methods are also discussed.

Abstract: The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, —C(?NR?)—NR?R? or —CH2—CH?CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infractions, such as drug-resistant bacterial infections.

Abstract: A semiconductor device package includes a substrate, a silicon (Si) or silicon carbide (SiC) semiconductor die, and a metal layer on a surface of the semiconductor die. The metal layer includes a bonding surface that is attached to a surface of the substrate by a die attach material. The bonding surface includes opposing edges that extend along a perimeter of the semiconductor die, and one or more non-orthogonal corners that are configured to reduce stress at an interface between the bonding surface and the die attach material. Related devices and fabrication methods are also discussed.

Abstract: A switch comprises a first wafer having a thin-film structure defined thereon, a second wafer having a plurality of features defined therein, and a seal between the first wafer and the second wafer forming a two-wafer structure having a liquid metal microswitch defined therebetween.

Abstract: An optical device is formed of two discrete relief structures to provide refractive and diffractive properties. A first discrete relief structure has a curved surface to provide the refractive properties, and a second discrete relief structure disposed over the first discrete relief structure includes one or more layers of an optically-transparent polymer material to provide the diffractive properties. The one or more layers in the second discrete relief structure define a surface curvature envelope formed of discontinuous diffractive features that produce the diffractive properties of the optical device.