Innate immune control of influenza virus interspecies adaptation.

Influenza virus pandemics are caused by viruses from animal reservoirs that adapt to efficiently infect and replicate in human hosts. Here, we investigated whether Interferon-Induced Transmembrane Protein 3 (IFITM3), a host antiviral factor with known human deficiencies, plays a role in interspecies virus infection and adaptation. We found that IFITM3-deficient mice and human cells could be infected with low doses of avian influenza viruses that failed to infect WT counterparts, identifying a new role for IFITM3 in controlling the minimum infectious viral dose threshold.

1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Expanding Structural Diversity and the Antibacterial Spectrum.

Antibacterial resistance continues its devastation of available therapies. Novel bacterial topoisomerase inhibitors (NBTIs) offer one solution to this critical issue. Two series of amine NBTIs bearing tricyclic DNA-binding moieties as well as amide NBTIs with a bicyclic DNA-binding moiety were synthesized and evaluated against methicillin-resistant (MRSA).

Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with Efficacy against MRSA.

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound .

CRISPR/Cas9 Genome Editing of the Human Topoisomerase II Intron 19 5' Splice Site Circumvents Etoposide Resistance in Human Leukemia K562 Cells.

An essential function of DNA topoisomerase II (TOP2; 170 kDa, TOP2/170) is to resolve DNA topologic entanglements during chromosome disjunction by introducing transient DNA double-stranded breaks. TOP2/170 is an important target for DNA damage-stabilizing anticancer drugs, whose clinical efficacy is compromised by drug resistance often associated with decreased TOP2/170 expression. We recently demonstrated that an etoposide-resistant K562 clonal subline, K/VP.

Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive .

In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant (MRSA).

Cascade optical coherence tomography (C-OCT).

Significant advances for optical systems in terms of both performance and packaging are enabled by freeform optical components. Yet, surface form metrology for freeform optics remains a challenge. We developed and investigated a point-cloud cascade optical coherence tomography (C-OCT) technique to address this metrology challenge.

Off-axis conics as base surfaces for freeform optics enable null testability.

When conducting interferometric tests of freeform optical surfaces, additional optical components, such as computer-generated holograms or deformable mirrors, are often necessary to achieve a null or quasi-null. These additional optical components increase both the cost and the difficulty of interferometric tests of freeform optical surfaces. In this paper, designs using off-axis segments of conics as base surfaces for freeforms are explored.

Novel bacterial topoisomerase inhibitors derived from isomannide.

A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC = 2 μg/mL) and other Gram-positive pathogens.

hsa-miR-9-3p and hsa-miR-9-5p as Post-Transcriptional Modulators of DNA Topoisomerase II in Human Leukemia K562 Cells with Acquired Resistance to Etoposide.

DNA topoisomerase II protein (TOP2) 170 kDa (TOP2/170) is an important target for anticancer agents whose efficacy is often attenuated by chemoresistance. Our laboratory has characterized acquired resistance to etoposide in human leukemia K562 cells. The clonal resistant subline K/VP.

System design of a single-shot reconfigurable null test using a spatial light modulator for freeform metrology.

We report the simulation of an adaptive interferometric null test using a high-definition phase-only spatial light modulator (SLM) to measure form and mid spatial frequencies of a freeform mirror with a sag departure of 150 μm from its base sphere. A state-of-the-art commercial SLM is modeled as a reconfigurable phase computer generated hologram (CGH) that generates a nulling phase function with close to an order of magnitude higher amplitude than deformable mirrors. The theoretical uncertainty in form measurement arising from pixelation and phase quantization of the SLM is 50.

Experimental investigation in nodal aberration theory (NAT) with a customized Ritchey-Chrétien system: third-order coma.

Nodal aberration theory (NAT) describes the aberration properties of optical systems without symmetry. NAT was fully described mathematically and investigated through real-ray tracing software, but an experimental investigation is yet to be realized. In this study, a two-mirror Ritchey-Chrétien telescope was designed and built, including testing of the mirrors in null configurations, for experimental investigation of NAT.

Design, fabrication, and testing of convex reflective diffraction gratings.

The convex reflective diffraction grating is an essential optical component that lends itself to various applications. In this work, we first outline the design principles of convex diffraction gratings from wavefront quality and efficiency perspectives. We then describe a unique fabrication method that allows for the machining of convex diffraction gratings with variable groove structure, which is extendable to rotationally non-symmetric convex diffraction grating substrates.